NM_001845.6:c.82A>G

Variant names:

• chr13-110306946-T-C
• rs886049964
• NM_001845.6:c.82A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001845.6(COL4A1):​c.82A>G​(p.Lys28Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000758 in 1,319,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K28K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: COL4A1 NM_001845.6 missense, splice_region
• Scores: Splicing: ADA: 0.0007780
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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]

COL4A2 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3029735).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001845.6. 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
	COL4A1	NM_001845.6	MANE Select	c.82A>G	p.Lys28Glu	missense splice_region	Exon 1 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.82A>G	p.Lys28Glu	missense splice_region	Exon 1 of 25	NP_001290039.1	P02462-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.82A>G	p.Lys28Glu	missense splice_region	Exon 1 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.82A>G	p.Lys28Glu	missense splice_region	Exon 1 of 25	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.82A>G	p.Lys28Glu	missense splice_region	Exon 1 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.58e-7 AC: 1 AN: 1319760 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 649802

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26864

American (AMR) AF: 0.00 AC: 0 AN: 28260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23332

East Asian (EAS) AF: 0.00 AC: 0 AN: 29038

South Asian (SAS) AF: 0.00 AC: 0 AN: 72334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1048440

Other (OTH) AF: 0.00 AC: 0 AN: 54766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)
-	1	-	Brain small vessel disease 1 with or without ocular anomalies (1)
-	1	-	not specified (1)
-	1	-	Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.73
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.38
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
Polyphen		0.96	P
Vest4		0.26
MutPred		0.31		Gain of catalytic residue at G33 (P = 0)
MVP		0.73
MPC		0.54
ClinPred		0.48	T
GERP RS		3.5
PromoterAI		0.070	Neutral
Varity_R		0.19
gMVP		0.39
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00078
dbscSNV1_RF	Benign	0.032
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: rs886049964; hg19: chr13-110959293; COSMIC: COSV64626058; COSMIC: COSV64626058;