NM_000092.5:c.3011C>T

Variant names:

• chr2-227051116-G-A
• rs1800517
• NM_000092.5:c.3011C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.3011C>T​(p.Pro1004Leu) variant causes a missense change. The variant allele was found at a frequency of 0.497 in 1,613,426 control chromosomes in the GnomAD database, including 201,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1004P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.51 (20139 hom., cov: 31)
  • Exomes 𝑓: 0.50 (180863 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.51
• Publications: 46 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=3.101142E-5).
• BP6: Variant 2-227051116-G-A is Benign according to our data. Variant chr2-227051116-G-A is described in ClinVar as Benign. ClinVar VariationId is 255028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.611 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.3011C>T	p.Pro1004Leu	missense	Exon 33 of 48	NP_000083.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.3011C>T	p.Pro1004Leu	missense	Exon 33 of 48	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77872 AN: 151810 Hom.: 20112 Cov.: 31

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.520 AC: 129808 AN: 249542 AF XY: 0.522

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.453

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.495 AC: 723660 AN: 1461498 Hom.: 180863 Cov.: 52 AF XY: 0.498 AC XY: 362087 AN XY: 727070

African (AFR) AF: 0.566 AC: 18955 AN: 33474

American (AMR) AF: 0.549 AC: 24542 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 15128 AN: 26130

East Asian (EAS) AF: 0.466 AC: 18504 AN: 39696

South Asian (SAS) AF: 0.638 AC: 55020 AN: 86252

European-Finnish (FIN) AF: 0.508 AC: 27148 AN: 53414

Middle Eastern (MID) AF: 0.510 AC: 2944 AN: 5768

European-Non Finnish (NFE) AF: 0.478 AC: 531186 AN: 1111650

Other (OTH) AF: 0.501 AC: 30233 AN: 60390

GnomAD4 genome AF: 0.513 AC: 77950 AN: 151928 Hom.: 20139 Cov.: 31 AF XY: 0.514 AC XY: 38160 AN XY: 74226

African (AFR) AF: 0.566 AC: 23470 AN: 41442

American (AMR) AF: 0.514 AC: 7841 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1929 AN: 3470

East Asian (EAS) AF: 0.468 AC: 2410 AN: 5152

South Asian (SAS) AF: 0.630 AC: 3032 AN: 4812

European-Finnish (FIN) AF: 0.499 AC: 5256 AN: 10530

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32477 AN: 67964

Other (OTH) AF: 0.500 AC: 1051 AN: 2100

Alfa AF: 0.488 Hom.: 70010

Bravo AF: 0.515

TwinsUK AF: 0.483 AC: 1790

ALSPAC AF: 0.470 AC: 1811

ESP6500AA AF: 0.582 AC: 2198

ESP6500EA AF: 0.489 AC: 4022

ExAC AF: 0.520 AC: 62858

Asia WGS AF: 0.563 AC: 1959 AN: 3478

EpiCase AF: 0.462

EpiControl AF: 0.476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	0.088
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.024
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.000031	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.63	P
Vest4		0.12
MPC		0.14
ClinPred		0.082	T
GERP RS		4.6
Varity_R		0.41
gMVP		0.28
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800517; hg19: chr2-227915832; COSMIC: COSV61632594;