chr13-110307009-C-G

Position:

• chr13-110307009-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.19G>C​(p.Val7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,473,912 control chromosomes in the GnomAD database, including 126,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11147 hom., cov: 34)
  • Exomes 𝑓: 0.41 (115178 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0290

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]

COL4A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL4A1. . Gene score misZ 3.0194 (greater than the threshold 3.09). Trascript score misZ 4.972 (greater than threshold 3.09). GenCC has associacion of gene with brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.
• BP4: Computational evidence support a benign effect (MetaRNN=3.4492954E-5).
• BP6: Variant 13-110307009-C-G is Benign according to our data. Variant chr13-110307009-C-G is described in ClinVar as [Benign]. Clinvar id is 193216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110307009-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.19G>C	p.Val7Leu	missense_variant	1/52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.19G>C	p.Val7Leu	missense_variant	1/25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.19G>C	p.Val7Leu	missense_variant	1/52	1	NM_001845.6	ENSP00000364979.4
COL4A1	ENST00000543140.6	c.19G>C	p.Val7Leu	missense_variant	1/25	1		ENSP00000443348.1
COL4A2	ENST00000400163.7	c.-44-851C>G		intron_variant		5		ENSP00000383027.4
COL4A1	ENST00000649738.1	n.149G>C		non_coding_transcript_exon_variant	1/31

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56421 AN: 151854 Hom.: 11156 Cov.: 34

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.429

GnomAD3 exomes AF: 0.435 AC: 36477 AN: 83772 Hom.: 8340 AF XY: 0.440 AC XY: 20975 AN XY: 47692

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.631

Gnomad SAS exome AF: 0.466

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.413 AC: 546481 AN: 1321950 Hom.: 115178 Cov.: 40 AF XY: 0.416 AC XY: 270622 AN XY: 651288

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.558

Gnomad4 EAS exome AF: 0.601

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.371 AC: 56406 AN: 151962 Hom.: 11147 Cov.: 34 AF XY: 0.372 AC XY: 27620 AN XY: 74272

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.406

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.474

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.413

Gnomad4 OTH AF: 0.424

Alfa AF: 0.380 Hom.: 1412

Bravo AF: 0.379

TwinsUK AF: 0.402 AC: 1489

ALSPAC AF: 0.407 AC: 1569

ExAC AF: 0.340 AC: 7121

Asia WGS AF: 0.500 AC: 1729 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2021	- -

Brain small vessel disease 1 with or without ocular anomalies Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Porencephalic cyst Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.64
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.000034	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.090	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.57	T;T
Sift4G	Benign	0.98	T;T
Polyphen		0.0010	B;.
Vest4		0.040
MPC		0.38
ClinPred		0.0022	T
GERP RS		1.5
Varity_R		0.026
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs9515185; hg19: chr13-110959356; COSMIC: COSV64624437; COSMIC: COSV64624437;