13-110306944-C-A

Variant names:

• chr13-110306944-C-A
• rs534258213
• NM_001845.6:c.84G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001845.6(COL4A1):​c.84G>T​(p.Lys28Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000757 in 1,320,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. K28E) 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: 0.9885
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.84G>T	p.Lys28Asn	missense splice_region	Exon 1 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.84G>T	p.Lys28Asn	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.84G>T	p.Lys28Asn	missense splice_region	Exon 1 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.84G>T	p.Lys28Asn	missense splice_region	Exon 1 of 25	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.84G>T	p.Lys28Asn	missense splice_region	Exon 1 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.57e-7 AC: 1 AN: 1320156 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 649988

African (AFR) AF: 0.00 AC: 0 AN: 26868

American (AMR) AF: 0.00 AC: 0 AN: 28292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23330

East Asian (EAS) AF: 0.00 AC: 0 AN: 29050

South Asian (SAS) AF: 0.00 AC: 0 AN: 72390

European-Finnish (FIN) AF: 0.0000306 AC: 1 AN: 32712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1048680

Other (OTH) AF: 0.00 AC: 0 AN: 54802

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0081	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Benign	0.93
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.34	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.35
Sift	Benign	0.45	T
Sift4G	Benign	0.50	T
Polyphen		0.98	D
Vest4		0.20
MutPred		0.39		Gain of catalytic residue at G33 (P = 0)
MVP		0.82
MPC		0.45
ClinPred		0.68	D
GERP RS		3.5
PromoterAI		0.14	Neutral
Varity_R		0.19
gMVP		0.37
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.010		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: rs534258213; hg19: chr13-110959291;