rs551695730

chr9-134813994-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000093.5(COL5A1):c.3864C>T(p.Gly1288=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000529 in 1,550,996 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.30

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-134813994-C-T is Benign according to our data. Variant chr9-134813994-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567302.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-3.3 with no splicing effect.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.3864C>T	p.Gly1288=	synonymous_variant	49/66	ENST00000371817.8
COL5A1	NM_001278074.1	c.3864C>T	p.Gly1288=	synonymous_variant	49/66
COL5A1	XM_017014266.3	c.3864C>T	p.Gly1288=	synonymous_variant	49/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.3864C>T	p.Gly1288=	synonymous_variant	49/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.3864C>T	p.Gly1288=	synonymous_variant	49/66	2		A2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000643 AC: 10 AN: 155432 Hom.: 0 AF XY: 0.0000852 AC XY: 7 AN XY: 82188

Gnomad AFR exome AF: 0.000118

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000515 AC: 72 AN: 1398688 Hom.: 0 Cov.: 32 AF XY: 0.0000638 AC XY: 44 AN XY: 689920

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.0000839

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000227

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

COL5A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.22
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: rs551695730; hg19: chr9-137705840; COSMIC: COSV65666056; COSMIC: COSV65666056;