13-110306958-G-T

Variant names:

• chr13-110306958-G-T
• rs1368341216
• NM_001845.6:c.70C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001845.6(COL4A1):​c.70C>A​(p.Arg24Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,323,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=1.64 with no splicing effect.

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.70C>A	p.Arg24Arg	synonymous	Exon 1 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.70C>A	p.Arg24Arg	synonymous	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.70C>A	p.Arg24Arg	synonymous	Exon 1 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.70C>A	p.Arg24Arg	synonymous	Exon 1 of 25	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.70C>A	p.Arg24Arg	synonymous	Exon 1 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1323010 Hom.: 0 Cov.: 30 AF XY: 0.00000153 AC XY: 1 AN XY: 651536

African (AFR) AF: 0.00 AC: 0 AN: 26932

American (AMR) AF: 0.00 AC: 0 AN: 28518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23434

East Asian (EAS) AF: 0.00 AC: 0 AN: 29198

South Asian (SAS) AF: 0.00 AC: 0 AN: 72864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4014

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1050274

Other (OTH) AF: 0.00 AC: 0 AN: 54964

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		1.6
PromoterAI		0.028	Neutral

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: rs1368341216; hg19: chr13-110959305;