rs77716946

Positions:

• chr9-134761904-G-A
• chr9-134761904-G-C

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.1936-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,612,444 control chromosomes in the GnomAD database, including 1,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (84 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1010 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.47

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=-0.91).
• BP6: Variant 9-134761904-G-A is Benign according to our data. Variant chr9-134761904-G-A is described in ClinVar as [Benign]. Clinvar id is 255058.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 = 0.0273 (4161/152326) while in subpopulation NFE AF= 0.0393 (2675/68030). AF 95% confidence interval is 0.0381. There are 84 homozygotes in gnomad4. There are 2045 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4161 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1936-21G>A		intron_variant		ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1936-21G>A		intron_variant			NP_001265003.1
COL5A1	XM_017014266.3	c.1936-21G>A		intron_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1936-21G>A		intron_variant		1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.1936-21G>A		intron_variant		2		ENSP00000360885	A2

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4163 AN: 152208 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0300 AC: 7534 AN: 250822 Hom.: 166 AF XY: 0.0305 AC XY: 4135 AN XY: 135786

Gnomad AFR exome AF: 0.00580

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0177

Gnomad FIN exome AF: 0.0497

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0332

GnomAD4 exome AF: 0.0349 AC: 51015 AN: 1460118 Hom.: 1010 Cov.: 31 AF XY: 0.0346 AC XY: 25161 AN XY: 726420

Gnomad4 AFR exome AF: 0.00487

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.0378

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.0168

Gnomad4 FIN exome AF: 0.0477

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0273 AC: 4161 AN: 152326 Hom.: 84 Cov.: 33 AF XY: 0.0275 AC XY: 2045 AN XY: 74480

Gnomad4 AFR AF: 0.00614

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0526

Gnomad4 NFE AF: 0.0393

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0257 Hom.: 25

Bravo AF: 0.0248

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Ehlers-Danlos syndrome, classic type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 31, 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	-0.91
CADD	Benign	0.011
DANN	Benign	0.62

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: rs77716946; hg19: chr9-137653750;