Genetic Variant COL6A5:p.Ala2589Ser (chr3-130471872-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278298.2(COL6A5):c.7765G>T(p.Ala2589Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2589T) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

COL6A5
NM_001278298.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.413

Publications

7 publications found

Variant links:

Genes affected

COL6A5 (HGNC:26674): (collagen type VI alpha 5 chain) This gene encodes a member of the collagen superfamily of proteins. The encoded protein contains multiple von Willebrand factor A-like domains and may interact with the alpha 1 and alpha 2 chains of collagen VI to form the complete collagen VI trimer. Polymorphisms in this gene may be linked to dermal phenotypes, such as eczema. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

COL6A5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09063086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A5	NM_001278298.2 link	c.7765G>T	p.Ala2589Ser	missense_variant	Exon 40 of 41	ENST00000373157.9	NP_001265227.1	A8TX70H0Y393
COL6A5	NR_022012.3 link	n.8103G>T		non_coding_transcript_exon_variant	Exon 40 of 42
COL6A5	NM_153264.7 link	c.7574+905G>T		intron_variant	Intron 39 of 39		NP_694996.5	A8TX70-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A5	ENST00000373157.9 link	c.7765G>T	p.Ala2589Ser	missense_variant	Exon 40 of 41	2	NM_001278298.2	ENSP00000362250.5	H0Y393
COL6A5	ENST00000312481.11 link	n.7765G>T		non_coding_transcript_exon_variant	Exon 40 of 42	1		ENSP00000309762.7	A8TX70-1
COL6A5	ENST00000512482.1 link	c.1270G>T	p.Ala424Ser	missense_variant	Exon 5 of 6	5		ENSP00000424968.1	H0Y9T2
COL6A5	ENST00000512836.6 link	c.7574+905G>T		intron_variant	Intron 39 of 39	2		ENSP00000422898.2	A8TX70-2H0Y935

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000139

AC:

AN:

72030

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000652

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.23e-7

AC:

AN:

1382822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31534

American (AMR)

AF:

0.0000280

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

35700

South Asian (SAS)

AF:

0.00

AC:

AN:

79200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078136

Other (OTH)

AF:

0.00

AC:

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.6

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

T;T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.45

T;T;T

M_CAP

Benign

0.080

MetaRNN

Benign

0.091

T;T;T

MetaSVM

Benign

-0.57

PhyloP100

0.41

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.41

.;N;N

REVEL

Benign

0.10

Sift

Benign

0.34

.;T;T

Sift4G

Benign

0.068

T;T;T

Vest4

0.099

MVP

0.31

MPC

0.033

ClinPred

0.064

GERP RS

1.2

gMVP

0.026

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over