rs16823264

Positions:

• chr2-227147467-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.17T>C​(p.Ile6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,334 control chromosomes in the GnomAD database, including 4,091 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (2111 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (1980 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.00400

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 -18 ACMG points.

• PM1: In a signal_peptide (size 37) in uniprot entity CO4A4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0058941543).
• BP6: Variant 2-227147467-A-G is Benign according to our data. Variant chr2-227147467-A-G is described in ClinVar as [Benign]. Clinvar id is 255016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227147467-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.17T>C	p.Ile6Thr	missense_variant	2/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.17T>C	p.Ile6Thr	missense_variant	2/48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.0924 AC: 14055 AN: 152066 Hom.: 2106 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0237 AC: 5903 AN: 249444 Hom.: 823 AF XY: 0.0185 AC XY: 2498 AN XY: 135328

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00972 AC: 14202 AN: 1461150 Hom.: 1980 Cov.: 30 AF XY: 0.00861 AC XY: 6258 AN XY: 726910

Gnomad4 AFR exome AF: 0.332

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000592

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0926 AC: 14087 AN: 152184 Hom.: 2111 Cov.: 32 AF XY: 0.0892 AC XY: 6637 AN XY: 74420

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0174 Hom.: 901

Bravo AF: 0.105

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.317 AC: 1216

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.0286 AC: 3451

Asia WGS AF: 0.0280 AC: 99 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ile6Thr in exon 2 of COL4A4: This variant is not expected to have clinical sig nificance because it has been identified in 37.44% (495/1322) of African chromos omes by the 1000 Genomes Project (Phase 3; dbSNP rs16823264). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2017	- -

Alport syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.49
DANN	Benign	0.69
DEOGEN2	Benign	0.069	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.33	N;.
REVEL	Benign	0.17
Sift	Benign	0.26	T;.
Sift4G	Uncertain	0.044	D;.
Polyphen		0.0	B;.
Vest4		0.077
MPC		0.18
ClinPred		0.0012	T
GERP RS		-2.4
Varity_R		0.043
gMVP		0.33

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: rs16823264; hg19: chr2-228012183;