rs369317619

Positions:

• chr9-134766989-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000093.5(COL5A1):​c.2134-11G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: COL5A1 NM_000093.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004250
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.16

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-134766989-G-C is Benign according to our data. Variant chr9-134766989-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 212891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2134-11G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2134-11G>C		splice_polypyrimidine_tract_variant, intron_variant			NP_001265003.1
COL5A1	XM_017014266.3	c.2134-11G>C		splice_polypyrimidine_tract_variant, intron_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2134-11G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.2134-11G>C		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000360885	A2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248352 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 134654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000982

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461108 Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 82 AN XY: 726814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000140

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2014	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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs369317619; hg19: chr9-137658835;