rs77104306

Positions:

chr2-227008171-C-T

Variant summary

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

The NM_000092.5(COL4A4):c.4656G>A(p.Met1552Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,614,082 control chromosomes in the GnomAD database, including 65 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 0.012 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 42 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.788

Variant links:

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010259122).

BP6

Variant 2-227008171-C-T is Benign according to our data. Variant chr2-227008171-C-T is described in ClinVar as [Benign]. Clinvar id is 334703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227008171-C-T is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.4656G>A	p.Met1552Ile	missense_variant	47/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.4656G>A	p.Met1552Ile	missense_variant	47/48	5	NM_000092.5	P1
COL4A4	ENST00000682098.1 linkuse as main transcript	c.258G>A	p.Met86Ile	missense_variant	2/3

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1889

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00319

AC:

795

AN:

248896

Hom.:

AF XY:

0.00231

AC XY:

312

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.0475

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00140

AC:

2048

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

847

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0528

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.0124

AC:

1891

AN:

152324

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

899

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0436

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.00515

Hom.:

Bravo

AF:

0.0141

ESP6500AA

AF:

0.0370

AC:

155

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00398

AC:

482

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Met1552Ile in exon 47 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 4.72% (458/9710) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs77104306). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 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	Invitae	Jan 31, 2024	- -

Alport syndrome

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 03, 2019	- -
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. -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.85

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.28

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.018

Polyphen

0.40

Vest4

0.36

MutPred

0.42

Loss of disorder (P = 0.0676);

MVP

0.66

MPC

0.16

ClinPred

0.025

GERP RS

3.1

Varity_R

0.46

gMVP

0.37

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