17-50188065-A-G

Variant names:

• chr17-50188065-A-G
• rs2586488
• NM_000088.4:c.3261+31T>C

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.3261+31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,612,540 control chromosomes in the GnomAD database, including 376,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33444 hom., cov: 33)
  • Exomes 𝑓: 0.68 (343528 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.761
• Publications: 36 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=-0.84).
• BP6: Variant 17-50188065-A-G is Benign according to our data. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188065-A-G is described in CliVar as Benign. Clinvar id is 674808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3261+31T>C		intron_variant	Intron 44 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.3063+31T>C		intron_variant	Intron 41 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.2991+31T>C		intron_variant	Intron 42 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.2343+31T>C		intron_variant	Intron 31 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3261+31T>C		intron_variant	Intron 44 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000511732.1	n.616T>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
COL1A1	ENST00000486572.1	n.459+31T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100302 AN: 152006 Hom.: 33421 Cov.: 33

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.684

GnomAD2 exomes AF: 0.670 AC: 166345 AN: 248426 AF XY: 0.668

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.527

Gnomad FIN exome AF: 0.702

Gnomad NFE exome AF: 0.693

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.684 AC: 999503 AN: 1460416 Hom.: 343528 Cov.: 43 AF XY: 0.681 AC XY: 494916 AN XY: 726378

African (AFR) AF: 0.581 AC: 19430 AN: 33446

American (AMR) AF: 0.722 AC: 32161 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 19453 AN: 26102

East Asian (EAS) AF: 0.556 AC: 22045 AN: 39662

South Asian (SAS) AF: 0.604 AC: 52067 AN: 86136

European-Finnish (FIN) AF: 0.701 AC: 37328 AN: 53270

Middle Eastern (MID) AF: 0.722 AC: 4163 AN: 5764

European-Non Finnish (NFE) AF: 0.695 AC: 771746 AN: 1111122

Other (OTH) AF: 0.681 AC: 41110 AN: 60346

GnomAD4 genome AF: 0.660 AC: 100370 AN: 152124 Hom.: 33444 Cov.: 33 AF XY: 0.660 AC XY: 49082 AN XY: 74356

African (AFR) AF: 0.581 AC: 24088 AN: 41494

American (AMR) AF: 0.717 AC: 10976 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2597 AN: 3472

East Asian (EAS) AF: 0.531 AC: 2736 AN: 5148

South Asian (SAS) AF: 0.615 AC: 2962 AN: 4814

European-Finnish (FIN) AF: 0.716 AC: 7588 AN: 10602

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 46999 AN: 67980

Other (OTH) AF: 0.683 AC: 1443 AN: 2112

Alfa AF: 0.683 Hom.: 138344

Bravo AF: 0.661

Asia WGS AF: 0.556 AC: 1935 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Osteogenesis imperfecta type III Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta with normal sclerae, dominant form Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta, perinatal lethal Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta type I Benign:1

Jul 22, 2021

Genome-Nilou Lab

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	-0.84
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2586488; hg19: chr17-48265426; COSMIC: COSV56803091; COSMIC: COSV56803091;