rs3752895

Variant names:

• chr2-227022057-A-G
• rs3752895
• NM_000092.5:c.4207T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-227022057-A-G
• chr2-227022057-A-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.4207T>C​(p.Ser1403Pro) variant causes a missense change. The variant allele was found at a frequency of 0.447 in 1,612,828 control chromosomes in the GnomAD database, including 164,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (19177 hom., cov: 31)
  • Exomes 𝑓: 0.44 (145151 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.74
• Publications: 44 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=7.318786E-5).
• BP6: Variant 2-227022057-A-G is Benign according to our data. Variant chr2-227022057-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 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.4207T>C	p.Ser1403Pro	missense	Exon 44 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.4207T>C	p.Ser1403Pro	missense	Exon 44 of 48	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74967 AN: 151788 Hom.: 19134 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.477 AC: 118999 AN: 249310 AF XY: 0.473

Gnomad AFR exome AF: 0.642

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.509

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.442 AC: 645388 AN: 1460922 Hom.: 145151 Cov.: 38 AF XY: 0.443 AC XY: 322051 AN XY: 726778

African (AFR) AF: 0.637 AC: 21321 AN: 33454

American (AMR) AF: 0.533 AC: 23851 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13454 AN: 26132

East Asian (EAS) AF: 0.411 AC: 16301 AN: 39694

South Asian (SAS) AF: 0.559 AC: 48237 AN: 86216

European-Finnish (FIN) AF: 0.495 AC: 26430 AN: 53406

Middle Eastern (MID) AF: 0.404 AC: 2331 AN: 5768

European-Non Finnish (NFE) AF: 0.420 AC: 466368 AN: 1111180

Other (OTH) AF: 0.449 AC: 27095 AN: 60362

GnomAD4 genome AF: 0.494 AC: 75056 AN: 151906 Hom.: 19177 Cov.: 31 AF XY: 0.494 AC XY: 36664 AN XY: 74228

African (AFR) AF: 0.630 AC: 26102 AN: 41444

American (AMR) AF: 0.480 AC: 7341 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1710 AN: 3468

East Asian (EAS) AF: 0.388 AC: 1989 AN: 5122

South Asian (SAS) AF: 0.550 AC: 2645 AN: 4810

European-Finnish (FIN) AF: 0.489 AC: 5151 AN: 10524

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28675 AN: 67938

Other (OTH) AF: 0.453 AC: 953 AN: 2104

Alfa AF: 0.444 Hom.: 53355

Bravo AF: 0.500

TwinsUK AF: 0.421 AC: 1560

ALSPAC AF: 0.415 AC: 1598

ESP6500AA AF: 0.608 AC: 2276

ESP6500EA AF: 0.419 AC: 3440

ExAC AF: 0.476 AC: 57469

Asia WGS AF: 0.483 AC: 1682 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.407

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)
-	-	1	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.33
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.000073	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	3.2	N
REVEL	Benign	0.23
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.071
MPC		0.18
ClinPred		0.0068	T
GERP RS		5.6
Varity_R		0.066
gMVP		0.18
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: rs3752895; hg19: chr2-227886773; COSMIC: COSV61629628;