rs16948767

Positions:

• chr17-50197931-T-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.642+18A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,074 control chromosomes in the GnomAD database, including 5,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2628 hom., cov: 31)
  • Exomes 𝑓: 0.031 (2967 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.760

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=-0.81).
• BP6: Variant 17-50197931-T-G is Benign according to our data. Variant chr17-50197931-T-G is described in ClinVar as [Benign]. Clinvar id is 254950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50197931-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.642+18A>C		intron_variant		ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.642+18A>C		intron_variant			XP_005257115.2
COL1A1	XM_005257059.5	c.642+18A>C		intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.642+18A>C		intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.642+18A>C		intron_variant		1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000495677.1	n.369+18A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17408 AN: 151992 Hom.: 2617 Cov.: 31

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.0572

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0831

GnomAD3 exomes AF: 0.0476 AC: 11935 AN: 250590 Hom.: 1166 AF XY: 0.0435 AC XY: 5913 AN XY: 135832

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.00625

Gnomad SAS exome AF: 0.0585

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0343

GnomAD4 exome AF: 0.0312 AC: 45538 AN: 1460964 Hom.: 2967 Cov.: 32 AF XY: 0.0313 AC XY: 22757 AN XY: 726896

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.0297

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.00642

Gnomad4 SAS exome AF: 0.0594

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.0460

GnomAD4 genome AF: 0.115 AC: 17446 AN: 152110 Hom.: 2628 Cov.: 31 AF XY: 0.112 AC XY: 8317 AN XY: 74372

Gnomad4 AFR AF: 0.351

Gnomad4 AMR AF: 0.0472

Gnomad4 ASJ AF: 0.0276

Gnomad4 EAS AF: 0.00926

Gnomad4 SAS AF: 0.0568

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0822

Alfa AF: 0.0872 Hom.: 411

Bravo AF: 0.127

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.57

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: rs16948767; hg19: chr17-48275292; COSMIC: COSV56806394; COSMIC: COSV56806394;