17-50189930-G-C

Variant names:

• chr17-50189930-G-C
• rs2075559
• NM_000088.4:c.2560-18C>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.2560-18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 1,612,158 control chromosomes in the GnomAD database, including 214,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (20984 hom., cov: 32)
  • Exomes 𝑓: 0.51 (193701 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.929
• Publications: 27 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=-0.77).
• BP6: Variant 17-50189930-G-C is Benign according to our data. Variant chr17-50189930-G-C is described in ClinVar as Benign. ClinVar VariationId is 254948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.2560-18C>G		intron	N/A	NP_000079.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.2560-18C>G		intron	N/A	ENSP00000225964.6

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79741 AN: 151782 Hom.: 20969 Cov.: 32

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.520

GnomAD2 exomes AF: 0.522 AC: 129504 AN: 248000 AF XY: 0.517

Gnomad AFR exome AF: 0.553

Gnomad AMR exome AF: 0.640

Gnomad ASJ exome AF: 0.524

Gnomad EAS exome AF: 0.521

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.496

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.513 AC: 749573 AN: 1460256 Hom.: 193701 Cov.: 52 AF XY: 0.512 AC XY: 371807 AN XY: 726348

African (AFR) AF: 0.563 AC: 18824 AN: 33454

American (AMR) AF: 0.634 AC: 28210 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13586 AN: 26120

East Asian (EAS) AF: 0.556 AC: 22040 AN: 39650

South Asian (SAS) AF: 0.518 AC: 44678 AN: 86192

European-Finnish (FIN) AF: 0.451 AC: 23954 AN: 53150

Middle Eastern (MID) AF: 0.474 AC: 2735 AN: 5766

European-Non Finnish (NFE) AF: 0.508 AC: 564414 AN: 1111080

Other (OTH) AF: 0.516 AC: 31132 AN: 60346

GnomAD4 genome AF: 0.525 AC: 79793 AN: 151902 Hom.: 20984 Cov.: 32 AF XY: 0.525 AC XY: 38965 AN XY: 74238

African (AFR) AF: 0.559 AC: 23152 AN: 41426

American (AMR) AF: 0.591 AC: 9020 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1857 AN: 3466

East Asian (EAS) AF: 0.524 AC: 2683 AN: 5124

South Asian (SAS) AF: 0.543 AC: 2614 AN: 4818

European-Finnish (FIN) AF: 0.463 AC: 4899 AN: 10576

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33772 AN: 67912

Other (OTH) AF: 0.519 AC: 1093 AN: 2104

Alfa AF: 0.430 Hom.: 2113

Bravo AF: 0.541

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Eurofins Ntd Llc (ga)

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.

Jul 26, 2017

Athena Diagnostics

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 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		0.93
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: rs2075559; hg19: chr17-48267291; COSMIC: COSV56805103; COSMIC: COSV56805103;