rs991189007

Variant names:

• chr13-110306985-C-A
• rs991189007
• NM_001845.6:c.43G>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110306985-C-A
• chr13-110306985-C-T

Variant summary

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

The NM_001845.6(COL4A1):​c.43G>T​(p.Ala15Ser) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=0.27364543).

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.43G>T	p.Ala15Ser	missense	Exon 1 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.43G>T	p.Ala15Ser	missense	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.43G>T	p.Ala15Ser	missense	Exon 1 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.43G>T	p.Ala15Ser	missense	Exon 1 of 25	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.43G>T	p.Ala15Ser	missense	Exon 1 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1324800 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 652640

African (AFR) AF: 0.00 AC: 0 AN: 26918

American (AMR) AF: 0.00 AC: 0 AN: 28528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23416

East Asian (EAS) AF: 0.00 AC: 0 AN: 29476

South Asian (SAS) AF: 0.00 AC: 0 AN: 73070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3972

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051526

Other (OTH) AF: 0.00 AC: 0 AN: 55036

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.15
Sift	Benign	0.46	T
Sift4G	Benign	0.47	T
Polyphen		0.28	B
Vest4		0.20
MutPred		0.46		Gain of disorder (P = 0.0373)
MVP		0.56
MPC		0.35
ClinPred		0.15	T
GERP RS		2.4
PromoterAI		0.0066	Neutral
Varity_R		0.072
gMVP		0.32
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs991189007; hg19: chr13-110959332;