rs41306395

Positions:

• chr9-134810351-G-A

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.3528+43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.048 in 1,601,092 control chromosomes in the GnomAD database, including 2,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (145 hom., cov: 34)
  • Exomes 𝑓: 0.049 (1890 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.991

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=-0.93).
• BP6: Variant 9-134810351-G-A is Benign according to our data. Variant chr9-134810351-G-A is described in ClinVar as [Benign]. Clinvar id is 255080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.3528+43G>A		intron_variant		ENST00000371817.8
COL5A1	NM_001278074.1	c.3528+43G>A		intron_variant
COL5A1	XM_017014266.3	c.3528+43G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.3528+43G>A		intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.3528+43G>A		intron_variant		2		A2
COL5A1	ENST00000463925.1	n.427G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5830 AN: 152206 Hom.: 145 Cov.: 34

Gnomad AFR AF: 0.00936

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0739

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0572

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0409 AC: 10148 AN: 247966 Hom.: 275 AF XY: 0.0411 AC XY: 5529 AN XY: 134534

Gnomad AFR exome AF: 0.00817

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.000440

Gnomad SAS exome AF: 0.0178

Gnomad FIN exome AF: 0.0708

Gnomad NFE exome AF: 0.0592

Gnomad OTH exome AF: 0.0468

GnomAD4 exome AF: 0.0490 AC: 71047 AN: 1448768 Hom.: 1890 Cov.: 29 AF XY: 0.0482 AC XY: 34766 AN XY: 720630

Gnomad4 AFR exome AF: 0.00790

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0387

Gnomad4 EAS exome AF: 0.000304

Gnomad4 SAS exome AF: 0.0171

Gnomad4 FIN exome AF: 0.0707

Gnomad4 NFE exome AF: 0.0552

Gnomad4 OTH exome AF: 0.0438

GnomAD4 genome AF: 0.0383 AC: 5830 AN: 152324 Hom.: 145 Cov.: 34 AF XY: 0.0380 AC XY: 2830 AN XY: 74492

Gnomad4 AFR AF: 0.00933

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0739

Gnomad4 NFE AF: 0.0572

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0454 Hom.: 34

Bravo AF: 0.0344

Asia WGS AF: 0.0150 AC: 51 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 26, 2018

- -

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	-0.93
CADD	Benign	0.0070
DANN	Benign	0.70

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: rs41306395; hg19: chr9-137702197;