rs41298367

Positions:

• chr9-134763761-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.2034+24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,609,602 control chromosomes in the GnomAD database, including 673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (36 hom., cov: 32)
  • Exomes 𝑓: 0.026 (637 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.71

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 9-134763761-C-T is Benign according to our data. Variant chr9-134763761-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0198 (3007/152102) while in subpopulation NFE AF= 0.0296 (2011/67976). AF 95% confidence interval is 0.0285. There are 36 homozygotes in gnomad4. There are 1437 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3007 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2034+24C>T		intron_variant		ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2034+24C>T		intron_variant			NP_001265003.1
COL5A1	XM_017014266.3	c.2034+24C>T		intron_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2034+24C>T		intron_variant		1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.2034+24C>T		intron_variant		2		ENSP00000360885	A2

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3008 AN: 151984 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0194 AC: 4860 AN: 250158 Hom.: 69 AF XY: 0.0192 AC XY: 2597 AN XY: 135426

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.00950

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00562

Gnomad FIN exome AF: 0.0359

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0264 AC: 38502 AN: 1457500 Hom.: 637 Cov.: 29 AF XY: 0.0256 AC XY: 18544 AN XY: 725256

Gnomad4 AFR exome AF: 0.00404

Gnomad4 AMR exome AF: 0.00833

Gnomad4 ASJ exome AF: 0.00874

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00556

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0198 AC: 3007 AN: 152102 Hom.: 36 Cov.: 32 AF XY: 0.0193 AC XY: 1437 AN XY: 74344

Gnomad4 AFR AF: 0.00569

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00457

Gnomad4 FIN AF: 0.0414

Gnomad4 NFE AF: 0.0296

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0216 Hom.: 8

Bravo AF: 0.0168

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0030
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41298367; hg19: chr9-137655607;