rs140109751

Positions:

• chr2-189034161-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_000393.5(COL5A2):​c.4409C>T​(p.Ala1470Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1470T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 8.13

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 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. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, COL5A2
• BP6: Variant 2-189034161-G-A is Benign according to our data. Variant chr2-189034161-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264358.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.4409C>T	p.Ala1470Val	missense_variant	54/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.4271C>T	p.Ala1424Val	missense_variant	57/57
COL5A2	XM_047443251.1	c.4271C>T	p.Ala1424Val	missense_variant	59/59
COL5A2	XM_047443252.1	c.4271C>T	p.Ala1424Val	missense_variant	58/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.4409C>T	p.Ala1470Val	missense_variant	54/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.3248C>T	p.Ala1083Val	missense_variant	47/47	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727140

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2015

The p.A1470V variant (also known as c.4409C>T), located in coding exon 54 of the COL5A2 gene, results from a C to T substitution at nucleotide position 4409. The alanine at codon 1470 is replaced by valine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs140109751. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Ehlers-Danlos syndrome, classic type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	2.0	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	N;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D;.;.
Sift4G	Benign	0.16	T;T;.
Polyphen		0.63	P;.;P
Vest4		0.20
MVP		0.56
MPC		0.26
ClinPred		0.91	D
GERP RS		4.2
Varity_R		0.21
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs140109751; hg19: chr2-189898887;