2-227002723-G-C

Position:

• chr2-227002723-G-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.*4602C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 152,710 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (490 hom., cov: 34)
  • Exomes 𝑓: 0.076 (1 hom.)
• Consequence: COL4A4 NM_000092.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.620

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]

COL4A4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-227002723-G-C is Benign according to our data. Variant chr2-227002723-G-C is described in ClinVar as [Benign]. Clinvar id is 334637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.*4602C>G		3_prime_UTR_variant	48/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625	c.*4602C>G		3_prime_UTR_variant	48/48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.0769 AC: 11700 AN: 152172 Hom.: 487 Cov.: 34

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0697

Gnomad ASJ AF: 0.0854

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.0984

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.0842

GnomAD4 exome AF: 0.0762 AC: 32 AN: 420 Hom.: 1 Cov.: 0 AF XY: 0.0547 AC XY: 14 AN XY: 256

Gnomad4 FIN exome AF: 0.0749

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.0769 AC: 11710 AN: 152290 Hom.: 490 Cov.: 34 AF XY: 0.0760 AC XY: 5661 AN XY: 74470

Gnomad4 AFR AF: 0.0474

Gnomad4 AMR AF: 0.0695

Gnomad4 ASJ AF: 0.0854

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.0989

Gnomad4 FIN AF: 0.0578

Gnomad4 NFE AF: 0.0900

Gnomad4 OTH AF: 0.0890

Alfa AF: 0.0722 Hom.: 45

Bravo AF: 0.0756

Asia WGS AF: 0.145 AC: 503 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alport syndrome Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.0
DANN	Benign	0.75

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: rs1054415; hg19: chr2-227867439;