rs3124308

Positions:

• chr9-134730187-A-G
• chr9-134730187-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.925-49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,602,426 control chromosomes in the GnomAD database, including 162,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13310 hom., cov: 33)
  • Exomes 𝑓: 0.45 (149176 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.61

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=-0.96).
• BP6: Variant 9-134730187-A-G is Benign according to our data. Variant chr9-134730187-A-G is described in ClinVar as [Benign]. Clinvar id is 255102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.925-49A>G		intron_variant		ENST00000371817.8
COL5A1	NM_001278074.1	c.925-49A>G		intron_variant
COL5A1	XM_017014266.3	c.925-49A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.925-49A>G		intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.925-49A>G		intron_variant		2		A2

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60643 AN: 151730 Hom.: 13293 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.449

GnomAD3 exomes AF: 0.479 AC: 116878 AN: 244116 Hom.: 29750 AF XY: 0.475 AC XY: 62973 AN XY: 132576

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.707

Gnomad ASJ exome AF: 0.626

Gnomad EAS exome AF: 0.466

Gnomad SAS exome AF: 0.468

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.488

GnomAD4 exome AF: 0.448 AC: 649650 AN: 1450578 Hom.: 149176 Cov.: 39 AF XY: 0.449 AC XY: 323938 AN XY: 722004

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.628

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.463

Gnomad4 NFE exome AF: 0.437

Gnomad4 OTH exome AF: 0.454

GnomAD4 genome AF: 0.400 AC: 60695 AN: 151848 Hom.: 13310 Cov.: 33 AF XY: 0.408 AC XY: 30242 AN XY: 74198

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.625

Gnomad4 EAS AF: 0.480

Gnomad4 SAS AF: 0.464

Gnomad4 FIN AF: 0.460

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.453

Alfa AF: 0.440 Hom.: 2865

Bravo AF: 0.402

Asia WGS AF: 0.507 AC: 1757 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

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. -

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	-0.96
CADD	Benign	0.60
DANN	Benign	0.48

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: rs3124308; hg19: chr9-137622033; COSMIC: COSV65673420; COSMIC: COSV65673420;