rs2586494

Variant names:

• chr17-50195794-A-C
• rs2586494
• NM_000088.4:c.1056+129T>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.1056+129T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,334,520 control chromosomes in the GnomAD database, including 479,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52550 hom., cov: 30)
  • Exomes 𝑓: 0.85 (427265 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.590
• 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• COL1A1-related Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

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

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

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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• osteogenesis imperfecta type 1

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: ClinGen, G2P, Orphanet
• 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=-0.87).
• BP6: Variant 17-50195794-A-C is Benign according to our data. Variant chr17-50195794-A-C is described in ClinVar as Benign. ClinVar VariationId is 1262303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.864 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.1056+129T>G		intron	N/A	NP_000079.2	P02452

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.1056+129T>G		intron	N/A	ENSP00000225964.6	P02452
	COL1A1	ENST00000861334.1		c.1056+129T>G		intron	N/A	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.1056+129T>G		intron	N/A	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.827 AC: 125678 AN: 151934 Hom.: 52501 Cov.: 30

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.822

Gnomad NFE AF: 0.870

Gnomad OTH AF: 0.817

GnomAD4 exome AF: 0.846 AC: 1000498 AN: 1182468 Hom.: 427265 Cov.: 16 AF XY: 0.841 AC XY: 499384 AN XY: 593554

African (AFR) AF: 0.801 AC: 21794 AN: 27210

American (AMR) AF: 0.788 AC: 28019 AN: 35544

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 20161 AN: 23840

East Asian (EAS) AF: 0.503 AC: 17543 AN: 34886

South Asian (SAS) AF: 0.712 AC: 53730 AN: 75506

European-Finnish (FIN) AF: 0.874 AC: 42474 AN: 48580

Middle Eastern (MID) AF: 0.830 AC: 3510 AN: 4228

European-Non Finnish (NFE) AF: 0.874 AC: 770923 AN: 881844

Other (OTH) AF: 0.833 AC: 42344 AN: 50830

GnomAD4 genome AF: 0.827 AC: 125783 AN: 152052 Hom.: 52550 Cov.: 30 AF XY: 0.823 AC XY: 61144 AN XY: 74302

African (AFR) AF: 0.803 AC: 33296 AN: 41440

American (AMR) AF: 0.804 AC: 12292 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2946 AN: 3470

East Asian (EAS) AF: 0.484 AC: 2491 AN: 5150

South Asian (SAS) AF: 0.717 AC: 3446 AN: 4806

European-Finnish (FIN) AF: 0.883 AC: 9356 AN: 10598

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.870 AC: 59114 AN: 67976

Other (OTH) AF: 0.815 AC: 1723 AN: 2114

Alfa AF: 0.853 Hom.: 99703

Bravo AF: 0.822

Asia WGS AF: 0.619 AC: 2157 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.60
PhyloP100		-0.59
Mutation Taster		=15/85	disease causing

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: rs2586494; hg19: chr17-48273155; COSMIC: COSV56805109; COSMIC: COSV56805109;