NM_000088.4:c.4249-12G>A

Variant names:

• chr17-50185660-C-T
• rs2249492
• NM_000088.4:c.4249-12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000088.4(COL1A1):​c.4249-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 1,612,456 control chromosomes in the GnomAD database, including 292,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22816 hom., cov: 29)
  • Exomes 𝑓: 0.60 (269622 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Scores: Splicing: ADA: 0.0001039
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0840
• Publications: 35 publications found

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A1 Gene-Disease associations (from GenCC):

• Caffey disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-50185660-C-T is Benign according to our data. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50185660-C-T is described in CliVar as Benign. Clinvar id is 197918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.4249-12G>A		intron_variant	Intron 50 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.4051-12G>A		intron_variant	Intron 47 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.3979-12G>A		intron_variant	Intron 48 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.3331-12G>A		intron_variant	Intron 37 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.4249-12G>A		intron_variant	Intron 50 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000510710.3	n.*184G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.528 AC: 79873 AN: 151354 Hom.: 22803 Cov.: 29

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.578

GnomAD2 exomes AF: 0.590 AC: 146373 AN: 247976 AF XY: 0.592

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.676

Gnomad ASJ exome AF: 0.691

Gnomad EAS exome AF: 0.516

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.604 AC: 882496 AN: 1460984 Hom.: 269622 Cov.: 69 AF XY: 0.602 AC XY: 437737 AN XY: 726712

African (AFR) AF: 0.265 AC: 8856 AN: 33480

American (AMR) AF: 0.671 AC: 29996 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 18158 AN: 26132

East Asian (EAS) AF: 0.549 AC: 21801 AN: 39700

South Asian (SAS) AF: 0.538 AC: 46374 AN: 86252

European-Finnish (FIN) AF: 0.625 AC: 32935 AN: 52668

Middle Eastern (MID) AF: 0.636 AC: 3670 AN: 5768

European-Non Finnish (NFE) AF: 0.616 AC: 684727 AN: 1111898

Other (OTH) AF: 0.596 AC: 35979 AN: 60386

GnomAD4 genome AF: 0.527 AC: 79899 AN: 151472 Hom.: 22816 Cov.: 29 AF XY: 0.530 AC XY: 39255 AN XY: 73998

African (AFR) AF: 0.283 AC: 11673 AN: 41200

American (AMR) AF: 0.648 AC: 9880 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2410 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2674 AN: 5132

South Asian (SAS) AF: 0.553 AC: 2634 AN: 4760

European-Finnish (FIN) AF: 0.638 AC: 6706 AN: 10516

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41847 AN: 67842

Other (OTH) AF: 0.578 AC: 1212 AN: 2096

Alfa AF: 0.575 Hom.: 5228

Bravo AF: 0.521

Asia WGS AF: 0.507 AC: 1766 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 04, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Infantile cortical hyperostosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Osteogenesis imperfecta type I Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.1
DANN	Benign	0.90
PhyloP100		-0.084
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2249492; hg19: chr17-48263021; COSMIC: COSV56804421; COSMIC: COSV56804421;