rs145806603

Positions:

• chr2-227078048-A-G

Variant summary

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

The NM_000092.5(COL4A4):​c.1833T>C​(p.Gly611=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,613,846 control chromosomes in the GnomAD database, including 57 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. G611G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (52 hom.)
• Consequence: COL4A4 NM_000092.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.653

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-227078048-A-G is Benign according to our data. Variant chr2-227078048-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 500055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227078048-A-G is described in Lovd as [Benign]. Variant chr2-227078048-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.653 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00473 (719/152028) while in subpopulation AMR AF= 0.00976 (149/15272). AF 95% confidence interval is 0.00848. There are 5 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.1833T>C	p.Gly611=	synonymous_variant	25/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.1833T>C	p.Gly611=	synonymous_variant	25/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 720 AN: 151912 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00977

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00468

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00523 AC: 1301 AN: 248678 Hom.: 12 AF XY: 0.00525 AC XY: 710 AN XY: 135148

Gnomad AFR exome AF: 0.000842

Gnomad AMR exome AF: 0.00435

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00777

GnomAD4 exome AF: 0.00448 AC: 6551 AN: 1461818 Hom.: 52 Cov.: 31 AF XY: 0.00450 AC XY: 3272 AN XY: 727216

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.0453

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.00473 AC: 719 AN: 152028 Hom.: 5 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74322

Gnomad4 AFR AF: 0.000772

Gnomad4 AMR AF: 0.00976

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00378

Gnomad4 NFE AF: 0.00468

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00746 Hom.: 7

Bravo AF: 0.00549

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00670

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	COL4A4: BP4, BP7, BS2 -
Likely 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	GeneDx	May 04, 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. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gly611Gly in exon 25 of COL4A4: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.69% (449/65490) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs145806603). -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 23, 2021

- -

Alport syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.29
DANN	Benign	0.35

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: rs145806603; hg19: chr2-227942764;