13-110152465-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001845.6(COL4A1):c.4797G>A(p.Ala1599=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,778 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1599A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.73

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 13-110152465-C-T is Benign according to our data. Variant chr13-110152465-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110152465-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000572 (87/152212) while in subpopulation NFE AF= 0.00104 (71/68038). AF 95% confidence interval is 0.000848. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.4797G>A	p.Ala1599=	synonymous_variant	51/52	ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.4797G>A	p.Ala1599=	synonymous_variant	51/52	1	NM_001845.6	P1
COL4A1	ENST00000650424.1	c.954G>A	p.Ala318=	synonymous_variant	9/10
COL4A1	ENST00000649720.1	n.965G>A		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000602 AC: 151 AN: 250880 Hom.: 0 AF XY: 0.000575 AC XY: 78 AN XY: 135686

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.000907

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00120 AC: 1753 AN: 1461566 Hom.: 3 Cov.: 32 AF XY: 0.00116 AC XY: 845 AN XY: 727096

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74360

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000676

EpiCase AF: 0.00115

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	COL4A1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Brain small vessel disease 1 with or without ocular anomalies Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	3.3
Dann	Benign	0.64

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: rs146638269; hg19: chr13-110804812; COSMIC: COSV65424636;