rs2586494

Positions:

• chr17-50195794-A-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1056+129T>G		intron_variant		ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.1056+129T>G		intron_variant			XP_005257115.2
COL1A1	XM_005257059.5	c.957+520T>G		intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.958-316T>G		intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1056+129T>G		intron_variant		1	NM_000088.4	ENSP00000225964	P1

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

Gnomad4 AFR exome AF: 0.801

Gnomad4 AMR exome AF: 0.788

Gnomad4 ASJ exome AF: 0.846

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.712

Gnomad4 FIN exome AF: 0.874

Gnomad4 NFE exome AF: 0.874

Gnomad4 OTH exome AF: 0.833

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

Gnomad4 AFR AF: 0.803

Gnomad4 AMR AF: 0.804

Gnomad4 ASJ AF: 0.849

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.883

Gnomad4 NFE AF: 0.870

Gnomad4 OTH AF: 0.815

Alfa AF: 0.859 Hom.: 71622

Bravo AF: 0.822

Asia WGS AF: 0.619 AC: 2157 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

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