rs12475686

Positions:

• chr2-227108907-A-G
• chr2-227108907-A-T

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.658-39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,597,318 control chromosomes in the GnomAD database, including 311,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (28778 hom., cov: 31)
  • Exomes 𝑓: 0.62 (282745 hom.)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.32

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=-0.83).
• BP6: Variant 2-227108907-A-G is Benign according to our data. Variant chr2-227108907-A-G is described in ClinVar as [Benign]. Clinvar id is 1184738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227108907-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.658-39T>C		intron_variant		ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.658-39T>C		intron_variant		5	NM_000092.5	ENSP00000379866	P1
COL4A4	ENST00000643379.1	c.658-39T>C		intron_variant				ENSP00000494516
COL4A4	ENST00000682248.1	n.759-39T>C		intron_variant, non_coding_transcript_variant
COL4A4	ENST00000684257.1	n.612-39T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93423 AN: 151828 Hom.: 28751 Cov.: 31

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.630

GnomAD3 exomes AF: 0.604 AC: 143686 AN: 237764 Hom.: 43589 AF XY: 0.607 AC XY: 78270 AN XY: 128946

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.601

Gnomad SAS exome AF: 0.564

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.624 AC: 901986 AN: 1445372 Hom.: 282745 Cov.: 29 AF XY: 0.623 AC XY: 448147 AN XY: 719214

Gnomad4 AFR exome AF: 0.599

Gnomad4 AMR exome AF: 0.512

Gnomad4 ASJ exome AF: 0.672

Gnomad4 EAS exome AF: 0.584

Gnomad4 SAS exome AF: 0.561

Gnomad4 FIN exome AF: 0.611

Gnomad4 NFE exome AF: 0.635

Gnomad4 OTH exome AF: 0.621

GnomAD4 genome AF: 0.615 AC: 93501 AN: 151946 Hom.: 28778 Cov.: 31 AF XY: 0.614 AC XY: 45564 AN XY: 74260

Gnomad4 AFR AF: 0.598

Gnomad4 AMR AF: 0.578

Gnomad4 ASJ AF: 0.670

Gnomad4 EAS AF: 0.617

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.622

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.633

Alfa AF: 0.632 Hom.: 22549

Bravo AF: 0.609

Asia WGS AF: 0.600 AC: 2084 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 81% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 75. Only high quality variants are reported. -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.1
DANN	Benign	0.39

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: rs12475686; hg19: chr2-227973623; COSMIC: COSV61632915;