13-110307021-G-T

Variant names:

• chr13-110307021-G-T
• rs751749989
• NM_001845.6:c.7C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001845.6(COL4A1):​c.7C>A​(p.Pro3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,464,626 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 2.70
• Publications: 4 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07972333).
• BP6: Variant 13-110307021-G-T is Benign according to our data. Variant chr13-110307021-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289628.

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.7C>A	p.Pro3Thr	missense	Exon 1 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.7C>A	p.Pro3Thr	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.7C>A	p.Pro3Thr	missense	Exon 1 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.7C>A	p.Pro3Thr	missense	Exon 1 of 25	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.7C>A	p.Pro3Thr	missense	Exon 1 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000587 AC: 47 AN: 80102 AF XY: 0.000568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000434

GnomAD4 exome AF: 0.000689 AC: 904 AN: 1312428 Hom.: 1 Cov.: 33 AF XY: 0.000675 AC XY: 436 AN XY: 646298

African (AFR) AF: 0.000188 AC: 5 AN: 26642

American (AMR) AF: 0.00 AC: 0 AN: 26570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23058

East Asian (EAS) AF: 0.00 AC: 0 AN: 28890

South Asian (SAS) AF: 0.000630 AC: 45 AN: 71392

European-Finnish (FIN) AF: 0.00237 AC: 77 AN: 32476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3870

European-Non Finnish (NFE) AF: 0.000718 AC: 750 AN: 1045228

Other (OTH) AF: 0.000497 AC: 27 AN: 54302

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74402

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000780 AC: 53 AN: 67980

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000794 Hom.: 0

Bravo AF: 0.000536

ExAC AF: 0.000227 AC: 5

Asia WGS AF: 0.000580 AC: 2 AN: 3464

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	1	Brain small vessel disease 1 with or without ocular anomalies (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)
-	1	-	COL4A1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Schizencephaly;C0423401:Retinal arterial tortuosity;C2673195:Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome;C3281105:Hemorrhage, intracerebral, susceptibility to;C4755307:Brain small vessel disease 1 with or without ocular anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.097	T
Polyphen		0.043	B
Vest4		0.19
MVP		0.60
MPC		0.43
ClinPred		0.057	T
GERP RS		1.6
PromoterAI		-0.073	Neutral
Varity_R		0.092
gMVP		0.56
Mutation Taster		=81/19	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: rs751749989; hg19: chr13-110959368;