rs528892434

Variant names:

• chr3-130376666-C-A
• rs528892434
• NM_001278298.2:c.497C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-130376666-C-A
• chr3-130376666-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001278298.2(COL6A5):​c.497C>A​(p.Ser166Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S166F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A5 NM_001278298.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278298.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A5	NM_001278298.2	MANE Select	c.497C>A	p.Ser166Tyr	missense	Exon 3 of 41	NP_001265227.1	H0Y393
	COL6A5	NM_153264.7		c.497C>A	p.Ser166Tyr	missense	Exon 3 of 40	NP_694996.5
	COL6A5	NR_022012.3		n.835C>A		non_coding_transcript_exon	Exon 3 of 42

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A5	ENST00000373157.9	TSL:2 MANE Select	c.497C>A	p.Ser166Tyr	missense	Exon 3 of 41	ENSP00000362250.5	H0Y393
	COL6A5	ENST00000312481.11	TSL:1	n.497C>A		non_coding_transcript_exon	Exon 3 of 42	ENSP00000309762.7	A8TX70-1
	COL6A5	ENST00000512836.6	TSL:2	c.497C>A	p.Ser166Tyr	missense	Exon 3 of 40	ENSP00000422898.2	A8TX70-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247636 AF XY: 0.00000743

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461206 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111612

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.0042	T
PhyloP100		2.2
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.76
MutPred		0.68		Loss of disorder (P = 0.0183)
MVP		0.65
MPC		0.26
ClinPred		0.60	D
GERP RS		3.4
gMVP		0.59
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs528892434; hg19: chr3-130095509;