13-110201467-G-T

Position:

chr13-110201467-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001845.6(COL4A1):c.1055C>A(p.Pro352Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL4A1
NM_001845.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.26

Variant links:

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]

COL4A1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the COL4A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 194 curated pathogenic missense variants (we use a threshold of 10). The gene has 77 curated benign missense variants. Gene score misZ: 3.0194 (below the threshold of 3.09). Trascript score misZ: 4.972 (above the threshold of 3.09). GenCC associations: The gene is linked to brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.1055C>A	p.Pro352Gln	missense_variant	19/52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.1055C>A	p.Pro352Gln	missense_variant	19/25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL4A1	ENST00000375820.10 link	c.1055C>A	p.Pro352Gln	missense_variant	19/52	1	NM_001845.6	ENSP00000364979.4	P02462-1
COL4A1	ENST00000543140.6 link	c.1055C>A	p.Pro352Gln	missense_variant	19/25	1		ENSP00000443348.1	P02462-2
COL4A1	ENST00000647797.1 link	c.932C>A	p.Pro311Gln	missense_variant	18/20			ENSP00000497756.2	A0A3B3ITG7
COL4A1	ENST00000649738.1 link	n.1185C>A		non_coding_transcript_exon_variant	19/31

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2023	Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2024	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 352 of the COL4A1 protein (p.Pro352Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL4A1 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.72

D;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.037

D;T

Polyphen

1.0

D;.

Vest4

0.28

MutPred

0.37

Gain of catalytic residue at Y348 (P = 0.0022);Gain of catalytic residue at Y348 (P = 0.0022);

MVP

0.87

MPC

0.36

ClinPred

0.76

GERP RS

3.9

Varity_R

0.10

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over