13-110192845-G-T

Variant names:

• chr13-110192845-G-T
• rs762408881
• NM_001845.6:c.1450C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001845.6(COL4A1):​c.1450C>A​(p.Pro484Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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]

ACMG classification

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 rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1450C>A	p.Pro484Thr	missense_variant	Exon 23 of 52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.1450C>A	p.Pro484Thr	missense_variant	Exon 23 of 25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1450C>A	p.Pro484Thr	missense_variant	Exon 23 of 52	1	NM_001845.6	ENSP00000364979.4
COL4A1	ENST00000543140.6	c.1450C>A	p.Pro484Thr	missense_variant	Exon 23 of 25	1		ENSP00000443348.1
COL4A1	ENST00000649738.1	n.1580C>A		non_coding_transcript_exon_variant	Exon 23 of 31

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Optic nerve hypoplasia Uncertain:1

-

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.73	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D;N
REVEL	Uncertain	0.62
Sift	Benign	0.41	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.96	D;.
Vest4		0.48
MutPred		0.44		Gain of catalytic residue at P479 (P = 2e-04);Gain of catalytic residue at P479 (P = 2e-04);
MVP		0.61
MPC		0.44
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.40

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: rs762408881; hg19: chr13-110845192;