rs16823264

Variant names:

• chr2-227147467-A-G
• rs16823264
• NM_000092.5:c.17T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.093 (2111 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (1980 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.00400
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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/Likely_benign. ClinVar VariationId is 255016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000092.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	NM_000092.5	MANE Select	c.17T>C	p.Ile6Thr	missense	Exon 2 of 48	NP_000083.3	P53420

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.17T>C	p.Ile6Thr	missense	Exon 2 of 48	ENSP00000379866.3	P53420
	COL4A4	ENST00000643379.1		c.17T>C	p.Ile6Thr	missense	Exon 2 of 15	ENSP00000494516.1	A0A2R8Y548
	COL4A4	ENST00000683508.1		c.17T>C	p.Ile6Thr	missense	Exon 1 of 2	ENSP00000506932.1	A0A804HI71

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

GnomAD2 exomes AF: 0.0237 AC: 5903 AN: 249444 AF XY: 0.0185

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 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

African (AFR) AF: 0.332 AC: 11013 AN: 33204

American (AMR) AF: 0.0165 AC: 736 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00441 AC: 380 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.0220 AC: 127 AN: 5766

European-Non Finnish (NFE) AF: 0.000592 AC: 658 AN: 1111724

Other (OTH) AF: 0.0211 AC: 1275 AN: 60324

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

African (AFR) AF: 0.321 AC: 13322 AN: 41454

American (AMR) AF: 0.0338 AC: 516 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 68032

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

Alfa AF: 0.0338 Hom.: 2793

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Alport syndrome (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.0040
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
PromoterAI		0.030	Neutral
Varity_R		0.043
gMVP		0.33
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16823264; hg19: chr2-228012183;