rs2075558

Positions:

• chr17-50190224-A-C
• chr17-50190224-A-G

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.2451+103T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,243,044 control chromosomes in the GnomAD database, including 96,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10477 hom., cov: 31)
  • Exomes 𝑓: 0.38 (86455 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11

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=-0.82).
• BP6: Variant 17-50190224-A-C is Benign according to our data. Variant chr17-50190224-A-C is described in ClinVar as [Benign]. Clinvar id is 1268888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2451+103T>G		intron_variant		ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.2451+103T>G		intron_variant			XP_005257115.2
COL1A1	XM_005257059.5	c.1533+103T>G		intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.2253+103T>G		intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2451+103T>G		intron_variant		1	NM_000088.4	ENSP00000225964	P1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53719 AN: 151536 Hom.: 10463 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.381 AC: 416358 AN: 1091392 Hom.: 86455 Cov.: 15 AF XY: 0.385 AC XY: 214498 AN XY: 557764

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.803

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.407

Gnomad4 NFE exome AF: 0.349

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.355 AC: 53774 AN: 151652 Hom.: 10477 Cov.: 31 AF XY: 0.366 AC XY: 27110 AN XY: 74118

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.785

Gnomad4 SAS AF: 0.488

Gnomad4 FIN AF: 0.413

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.366

Alfa AF: 0.357 Hom.: 1267

Bravo AF: 0.354

Asia WGS AF: 0.613 AC: 2128 AN: 3476

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 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.8
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2075558; hg19: chr17-48267585; COSMIC: COSV56808761; COSMIC: COSV56808761;