2-227003003-G-A

Variant names:

• chr2-227003003-G-A
• rs1054413
• NM_000092.5:c.*4322C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.*4322C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 152,494 control chromosomes in the GnomAD database, including 19,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19876 hom., cov: 33)
  • Exomes 𝑓: 0.46 (41 hom.)
• Consequence: COL4A4 NM_000092.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.605

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-227003003-G-A is Benign according to our data. Variant chr2-227003003-G-A is described in ClinVar as [Benign]. Clinvar id is 334644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.*4322C>T		3_prime_UTR_variant	Exon 48 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625	c.*4322C>T		3_prime_UTR_variant	Exon 48 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75769 AN: 151956 Hom.: 19834 Cov.: 33

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.471

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: 0.456

GnomAD4 exome AF: 0.462 AC: 194 AN: 420 Hom.: 41 Cov.: 0 AF XY: 0.468 AC XY: 117 AN XY: 250

Gnomad4 FIN exome AF: 0.464

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.499 AC: 75859 AN: 152074 Hom.: 19876 Cov.: 33 AF XY: 0.499 AC XY: 37077 AN XY: 74334

Gnomad4 AFR AF: 0.672

Gnomad4 AMR AF: 0.472

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: 0.451

Alfa AF: 0.420 Hom.: 19648

Bravo AF: 0.505

Asia WGS AF: 0.491 AC: 1710 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alport syndrome Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.5
DANN	Benign	0.76

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: rs1054413; hg19: chr2-227867719; COSMIC: COSV58131351; COSMIC: COSV58131351;