NM_000093.5:c.1787T>C

Variant names:

• chr9-134754286-T-C
• rs754773665
• NM_000093.5:c.1787T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_000093.5(COL5A1):​c.1787T>C​(p.Val596Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V596V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.16

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32814807).
• BP6: Variant 9-134754286-T-C is Benign according to our data. Variant chr9-134754286-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409111.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1787T>C	p.Val596Ala	missense_variant	Exon 16 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1787T>C	p.Val596Ala	missense_variant	Exon 16 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.1787T>C	p.Val596Ala	missense_variant	Exon 16 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1787T>C	p.Val596Ala	missense_variant	Exon 16 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.1787T>C	p.Val596Ala	missense_variant	Exon 16 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250574 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461622 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Sep 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V596A variant (also known as c.1787T>C), located in coding exon 16 of the COL5A1 gene, results from a T to C substitution at nucleotide position 1787. The valine at codon 596 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Feb 10, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V596A variant in the COL5A1 gene has not been reported previously as a pathogenic variant,nor as a benign variant, to our knowledge. The V596A variant is not observed in large populationcohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). TheV596A variant is a conservative amino acid substitution, which occurs at a position that is notconserved. In silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. We interpret V596A as a variant of uncertain significance. -

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

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.88	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.16	B;.
Vest4		0.43
MutPred		0.26		Gain of methylation at R594 (P = 0.0884);Gain of methylation at R594 (P = 0.0884);
MVP		0.73
MPC		1.6
ClinPred		0.29	T
GERP RS		5.0
Varity_R		0.048
gMVP		0.34

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: rs754773665; hg19: chr9-137646132;