3-130376426-C-T

Position:

• chr3-130376426-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001278298.2(COL6A5):​c.257C>T​(p.Thr86Ile) 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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A5 NM_001278298.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41674393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A5	NM_001278298.2	c.257C>T	p.Thr86Ile	missense_variant	3/41	ENST00000373157.9	NP_001265227.1
COL6A5	NM_153264.7	c.257C>T	p.Thr86Ile	missense_variant	3/40		NP_694996.5
COL6A5	NR_022012.3	n.595C>T		non_coding_transcript_exon_variant	3/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A5	ENST00000373157.9	c.257C>T	p.Thr86Ile	missense_variant	3/41	2	NM_001278298.2	ENSP00000362250	P2
COL6A5	ENST00000312481.11	c.257C>T	p.Thr86Ile	missense_variant, NMD_transcript_variant	3/42	1		ENSP00000309762
COL6A5	ENST00000512836.6	c.257C>T	p.Thr86Ile	missense_variant	3/40	2		ENSP00000422898	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.257C>T (p.T86I) alteration is located in exon 3 (coding exon 2) of the COL6A5 gene. This alteration results from a C to T substitution at nucleotide position 257, causing the threonine (T) at amino acid position 86 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.015
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.39
MutPred		0.51		Loss of disorder (P = 0.0303);
MVP		0.52
MPC		0.15
ClinPred		0.86	D
GERP RS		4.2
gMVP		0.28

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: rs1173403411; hg19: chr3-130095269;