13-110306982-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001845.6(COL4A1):c.46C>G(p.Leu16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000226 in 1,325,216 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

Genes affected

COL4A1 (HGNC:2202): (collagen type IV alpha 1 chain) This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [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, COL4A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.33507648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.46C>G	p.Leu16Val	missense_variant	1/52	ENST00000375820.10
COL4A1	NM_001303110.2	c.46C>G	p.Leu16Val	missense_variant	1/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.46C>G	p.Leu16Val	missense_variant	1/52	1	NM_001845.6	P1
COL4A1	ENST00000543140.6	c.46C>G	p.Leu16Val	missense_variant	1/25	1
COL4A2	ENST00000400163.7	c.-44-878G>C		intron_variant		5
COL4A1	ENST00000649738.1	n.176C>G		non_coding_transcript_exon_variant	1/31

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000117 AC: 1 AN: 85304 Hom.: 0 AF XY: 0.0000207 AC XY: 1 AN XY: 48370

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: 0.0000570

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000226 AC: 3 AN: 1325216 Hom.: 0 Cov.: 30 AF XY: 0.00000306 AC XY: 2 AN XY: 652894

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: 0.0000137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000363

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000312 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 18, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 2144642). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. This variant is present in population databases (rs758399067, gnomAD 0.006%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 16 of the COL4A1 protein (p.Leu16Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Benign	0.71
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.070	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.28	T;D
Sift4G	Benign	0.87	T;T
Polyphen		0.96	P;.
Vest4		0.18
MutPred		0.47		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.45
MPC		0.39
ClinPred		0.32	T
GERP RS		3.3
Varity_R		0.086
gMVP		0.31

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: rs758399067; hg19: chr13-110959329;