Genetic Variant COL4A1:c.4641-32G>A (chr13-110155429-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001845.6(COL4A1):c.4641-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,554,910 control chromosomes in the GnomAD database, including 2,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 1394 hom., cov: 33)

Exomes 𝑓: 0.015 ( 1195 hom. )

Consequence

COL4A1
NM_001845.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.89

Variant links:

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]

COL4A1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 13-110155429-C-T is Benign according to our data. Variant chr13-110155429-C-T is described in ClinVar as [Benign]. Clinvar id is 1298231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.4641-32G>A		intron_variant	Intron 49 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A1	ENST00000375820.10 link	c.4641-32G>A	intron_variant	Intron 49 of 51	1	NM_001845.6	ENSP00000364979.4	P02462-1
COL4A1	ENST00000650424.1 link	c.795-32G>A	intron_variant	Intron 7 of 9			ENSP00000497477.2	A0A3B3ISV3
COL4A1	ENST00000649720.1 link	n.809-32G>A	intron_variant	Intron 4 of 6

Frequencies

GnomAD3 genomes

AF:

0.0778

AC:

11835

AN:

152148

Hom.:

1387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0317

Gnomad ASJ

AF:

0.0306

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00934

Gnomad OTH

AF:

0.0651

GnomAD3 exomes

AF:

0.0257

AC:

6151

AN:

239142

Hom.:

467

AF XY:

0.0212

AC XY:

2746

AN XY:

129424

show subpopulations

Gnomad AFR exome

AF:

0.254

Gnomad AMR exome

AF:

0.0213

Gnomad ASJ exome

AF:

0.0376

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00413

Gnomad FIN exome

AF:

0.00215

Gnomad NFE exome

AF:

0.00911

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0150

AC:

21047

AN:

1402644

Hom.:

1195

Cov.:

AF XY:

0.0140

AC XY:

9815

AN XY:

700540

show subpopulations

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.0222

Gnomad4 ASJ exome

AF:

0.0348

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00466

Gnomad4 FIN exome

AF:

0.00166

Gnomad4 NFE exome

AF:

0.00812

Gnomad4 OTH exome

AF:

0.0257

GnomAD4 genome

AF:

0.0780

AC:

11878

AN:

152266

Hom.:

1394

Cov.:

AF XY:

0.0741

AC XY:

5516

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.252

Gnomad4 AMR

AF:

0.0315

Gnomad4 ASJ

AF:

0.0306

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00434

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00934

Gnomad4 OTH

AF:

0.0644

Alfa

AF:

0.0340

Hom.:

100

Bravo

AF:

0.0876

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.013

DANN

Benign

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over