NM_000088.4:c.299-20C>G

Variant names:

• chr17-50199610-G-C
• rs2256835
• NM_000088.4:c.299-20C>G

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.299-20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,613,412 control chromosomes in the GnomAD database, including 347,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (25709 hom., cov: 32)
  • Exomes 𝑓: 0.66 (322222 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.238
• Publications: 18 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=-0.8).
• BP6: Variant 17-50199610-G-C is Benign according to our data. Variant chr17-50199610-G-C is described in ClinVar as Benign. ClinVar VariationId is 254949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.299-20C>G		intron_variant	Intron 2 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.299-20C>G		intron_variant	Intron 2 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.299-20C>G		intron_variant	Intron 2 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.299-20C>G		intron_variant	Intron 2 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.299-20C>G		intron_variant	Intron 2 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000507689.1	c.353-20C>G		intron_variant	Intron 1 of 3	2		ENSP00000460459.1
COL1A1	ENST00000474644.1	n.418-20C>G		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84198 AN: 151886 Hom.: 25697 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.551

GnomAD2 exomes AF: 0.626 AC: 157107 AN: 250922 AF XY: 0.632

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.594

Gnomad ASJ exome AF: 0.642

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.726

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.637

GnomAD4 exome AF: 0.660 AC: 964366 AN: 1461410 Hom.: 322222 Cov.: 62 AF XY: 0.660 AC XY: 479498 AN XY: 727018

African (AFR) AF: 0.267 AC: 8951 AN: 33466

American (AMR) AF: 0.588 AC: 26263 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 16853 AN: 26128

East Asian (EAS) AF: 0.601 AC: 23839 AN: 39684

South Asian (SAS) AF: 0.609 AC: 52481 AN: 86228

European-Finnish (FIN) AF: 0.717 AC: 38303 AN: 53400

Middle Eastern (MID) AF: 0.586 AC: 3340 AN: 5704

European-Non Finnish (NFE) AF: 0.680 AC: 756004 AN: 1111742

Other (OTH) AF: 0.635 AC: 38332 AN: 60370

GnomAD4 genome AF: 0.554 AC: 84232 AN: 152002 Hom.: 25709 Cov.: 32 AF XY: 0.557 AC XY: 41392 AN XY: 74288

African (AFR) AF: 0.279 AC: 11564 AN: 41458

American (AMR) AF: 0.559 AC: 8539 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2283 AN: 3466

East Asian (EAS) AF: 0.627 AC: 3242 AN: 5168

South Asian (SAS) AF: 0.614 AC: 2955 AN: 4812

European-Finnish (FIN) AF: 0.748 AC: 7885 AN: 10548

Middle Eastern (MID) AF: 0.572 AC: 167 AN: 292

European-Non Finnish (NFE) AF: 0.673 AC: 45751 AN: 67946

Other (OTH) AF: 0.551 AC: 1165 AN: 2114

Alfa AF: 0.619 Hom.: 5592

Bravo AF: 0.529

Asia WGS AF: 0.592 AC: 2061 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 28, 2017

Athena Diagnostics

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

- -

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. -

Osteogenesis imperfecta type I Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Osteogenesis imperfecta, perinatal lethal 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	-0.80
CADD	Benign	6.8
DANN	Benign	0.47
PhyloP100		0.24
Mutation Taster		=99/1	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: rs2256835; hg19: chr17-48276971; COSMIC: COSV56806200; COSMIC: COSV56806200;