Genetic Variant NM_001845.6:c.1728+57T>C (chr13-110187081-A-G) – 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.1728+57T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,588,336 control chromosomes in the GnomAD database, including 108,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11633 hom., cov: 33)

Exomes 𝑓: 0.37 ( 97348 hom. )

Consequence

COL4A1
NM_001845.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.20

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=-0.91).

BP6

Variant 13-110187081-A-G is Benign according to our data. Variant chr13-110187081-A-G is described in ClinVar as [Benign]. Clinvar id is 1293311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.1728+57T>C		intron_variant	Intron 25 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.1728+57T>C		intron_variant	Intron 25 of 51	1	NM_001845.6	ENSP00000364979.4		P02462-1
COL4A1	ENST00000649738.1 link	n.1858+57T>C		intron_variant	Intron 25 of 30

Frequencies

GnomAD3 genomes

AF:

0.389

AC:

59119

AN:

151826

Hom.:

11611

Cov.:

show subpopulations

Gnomad AFR

AF:

0.448

Gnomad AMI

AF:

0.607

Gnomad AMR

AF:

0.376

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.451

Gnomad SAS

AF:

0.342

Gnomad FIN

AF:

0.341

Gnomad MID

AF:

0.299

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.383

GnomAD4 exome

AF:

0.366

AC:

525896

AN:

1436390

Hom.:

97348

AF XY:

0.365

AC XY:

261283

AN XY:

716260

show subpopulations

Gnomad4 AFR exome

AF:

0.450

Gnomad4 AMR exome

AF:

0.404

Gnomad4 ASJ exome

AF:

0.304

Gnomad4 EAS exome

AF:

0.434

Gnomad4 SAS exome

AF:

0.338

Gnomad4 FIN exome

AF:

0.345

Gnomad4 NFE exome

AF:

0.365

Gnomad4 OTH exome

AF:

0.368

GnomAD4 genome

AF:

0.390

AC:

59196

AN:

151946

Hom.:

11633

Cov.:

AF XY:

0.388

AC XY:

28799

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.448

Gnomad4 AMR

AF:

0.376

Gnomad4 ASJ

AF:

0.325

Gnomad4 EAS

AF:

0.451

Gnomad4 SAS

AF:

0.343

Gnomad4 FIN

AF:

0.341

Gnomad4 NFE

AF:

0.364

Gnomad4 OTH

AF:

0.388

Alfa

AF:

0.365

Hom.:

17355

Bravo

AF:

0.397

Asia WGS

AF:

0.421

AC:

1464

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.46

DANN

Benign

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

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

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