rs45622539

Positions:

• chr9-134767390-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.2232+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,598,972 control chromosomes in the GnomAD database, including 582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (46 hom., cov: 33)
  • Exomes 𝑓: 0.026 (536 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0170

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=-0.89).
• BP6: Variant 9-134767390-C-T is Benign according to our data. Variant chr9-134767390-C-T is described in ClinVar as [Benign]. Clinvar id is 255061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0249 (3794/152258) while in subpopulation EAS AF= 0.0529 (273/5164). AF 95% confidence interval is 0.0477. There are 46 homozygotes in gnomad4. There are 1868 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3794 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2232+36C>T		intron_variant		ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2232+36C>T		intron_variant			NP_001265003.1
COL5A1	XM_017014266.3	c.2232+36C>T		intron_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2232+36C>T		intron_variant		1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.2232+36C>T		intron_variant		2		ENSP00000360885	A2

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3793 AN: 152140 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0264 AC: 6599 AN: 249828 Hom.: 106 AF XY: 0.0265 AC XY: 3583 AN XY: 135278

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0568

Gnomad SAS exome AF: 0.0240

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0256 AC: 36994 AN: 1446714 Hom.: 536 Cov.: 30 AF XY: 0.0256 AC XY: 18426 AN XY: 720464

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0195

Gnomad4 EAS exome AF: 0.0399

Gnomad4 SAS exome AF: 0.0244

Gnomad4 FIN exome AF: 0.0294

Gnomad4 NFE exome AF: 0.0254

Gnomad4 OTH exome AF: 0.0286

GnomAD4 genome AF: 0.0249 AC: 3794 AN: 152258 Hom.: 46 Cov.: 33 AF XY: 0.0251 AC XY: 1868 AN XY: 74452

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.0529

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0321

Gnomad4 NFE AF: 0.0258

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0268 Hom.: 13

Bravo AF: 0.0232

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 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	-0.89
CADD	Benign	2.3
DANN	Benign	0.37

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: rs45622539; hg19: chr9-137659236; COSMIC: COSV65671903;