2-227008312-A-G

Variant names:

• chr2-227008312-A-G
• rs13419076
• NM_000092.5:c.4523-8T>C

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.4523-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,611,954 control chromosomes in the GnomAD database, including 156,585 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18034 hom., cov: 34)
  • Exomes 𝑓: 0.43 (138551 hom.)
• Consequence: COL4A4 NM_000092.5 splice_region, intron
• Scores: Splicing: ADA: 0.000007093
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.81

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 (BayesDel_noAF=-0.85).
• BP6: Variant 2-227008312-A-G is Benign according to our data. Variant chr2-227008312-A-G is described in ClinVar as [Benign]. Clinvar id is 255040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227008312-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4523-8T>C		splice_region_variant, intron_variant	Intron 46 of 47	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4523-8T>C		splice_region_variant, intron_variant	Intron 46 of 47	5	NM_000092.5	ENSP00000379866.3
COL4A4	ENST00000682098.1	c.190-73T>C		intron_variant	Intron 1 of 2			ENSP00000508331.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72851 AN: 152014 Hom.: 17993 Cov.: 34

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.442

GnomAD3 exomes AF: 0.467 AC: 115265 AN: 246872 Hom.: 27557 AF XY: 0.464 AC XY: 62327 AN XY: 134204

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.393

Gnomad SAS exome AF: 0.578

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.431 AC: 629592 AN: 1459822 Hom.: 138551 Cov.: 46 AF XY: 0.434 AC XY: 314976 AN XY: 726242

Gnomad4 AFR exome AF: 0.602

Gnomad4 AMR exome AF: 0.525

Gnomad4 ASJ exome AF: 0.464

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.578

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.435

GnomAD4 genome AF: 0.479 AC: 72941 AN: 152132 Hom.: 18034 Cov.: 34 AF XY: 0.480 AC XY: 35686 AN XY: 74378

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.467

Gnomad4 ASJ AF: 0.447

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.574

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.436

Alfa AF: 0.445 Hom.: 7202

Bravo AF: 0.483

Asia WGS AF: 0.486 AC: 1692 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4523-8T>C in intron 46 of COL4A4: This variant is not expected to have clinica l significance because a T>C change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 64.07% (847/1322) of African chromosomes by the 1000 Genomes Pr oject (Phase 3; dbSNP rs13419076). -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 70% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 65. Only high quality variants are reported. -

Nov 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 provided Benign:3

Apr 03, 2017

Athena Diagnostics

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs13419076; hg19: chr2-227873028;