rs77104306

Positions:

• chr2-227008171-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.788

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 -18 ACMG points.

• PM1: In a domain Collagen IV NC1 (size 225) in uniprot entity CO4A4_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) in NM_000092.5
• 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	Protein	UniProt
COL4A4	NM_000092.5	c.4656G>A	p.Met1552Ile	missense_variant	47/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4656G>A	p.Met1552Ile	missense_variant	47/48	5	NM_000092.5	ENSP00000379866	P1
COL4A4	ENST00000682098.1	c.258G>A	p.Met86Ile	missense_variant	2/3			ENSP00000508331

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152206 Hom.: 23 Cov.: 33

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.: 10 AF XY: 0.00231 AC XY: 312 AN XY: 135248

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.: 42 Cov.: 32 AF XY: 0.00116 AC XY: 847 AN XY: 727162

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.: 23 Cov.: 33 AF XY: 0.0121 AC XY: 899 AN XY: 74492

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.: 8

Bravo AF: 0.0141

ESP6500AA AF: 0.0370 AC: 155

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00398 AC: 482

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	- -

Alport syndrome 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, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 03, 2019	- -

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Polyphen		0.40	B
Vest4		0.36
MutPred		0.42		Loss of disorder (P = 0.0676);
MVP		0.66
MPC		0.16
ClinPred		0.025	T
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

Other links and lift over

dbSNP: rs77104306; hg19: chr2-227872887;