rs36121515

chr2-227059512-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):c.2276C>T(p.Pro759Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,614,026 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P759P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (182 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (141 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.57

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006734222).
• BP6: Variant 2-227059512-G-A is Benign according to our data. Variant chr2-227059512-G-A is described in ClinVar as [Benign]. Clinvar id is 255019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227059512-G-A is described in Lovd as [Benign]. Variant chr2-227059512-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.2276C>T	p.Pro759Leu	missense_variant	28/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.2276C>T	p.Pro759Leu	missense_variant	28/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3807 AN: 152052 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0873

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.00652 AC: 1628 AN: 249558 Hom.: 59 AF XY: 0.00493 AC XY: 667 AN XY: 135396

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00272 AC: 3982 AN: 1461856 Hom.: 141 Cov.: 32 AF XY: 0.00236 AC XY: 1719 AN XY: 727226

Gnomad4 AFR exome AF: 0.0903

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000331

Gnomad4 OTH exome AF: 0.00560

GnomAD4 genome AF: 0.0251 AC: 3817 AN: 152170 Hom.: 182 Cov.: 32 AF XY: 0.0234 AC XY: 1743 AN XY: 74392

Gnomad4 AFR AF: 0.0873

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00581 Hom.: 52

Bravo AF: 0.0283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0841 AC: 308

ESP6500EA AF: 0.000614 AC: 5

ExAC AF: 0.00776 AC: 937

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro759Leu in exon 28 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 8.87% (867/9776) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs36121515). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.012	D
Polyphen		0.91	P
Vest4		0.37
MVP		0.77
MPC		0.58
ClinPred		0.055	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.28

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

Other links and lift over

dbSNP: rs36121515; hg19: chr2-227924228; COSMIC: COSV61632908;