NM_000092.5:c.4041A>T

Variant names:

• chr2-227027942-T-A
• rs16823077
• NM_000092.5:c.4041A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000092.5(COL4A4):​c.4041A>T​(p.Leu1347Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. L1347L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.629
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0636417).

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.4041A>T	p.Leu1347Phe	missense	Exon 42 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.4041A>T	p.Leu1347Phe	missense	Exon 42 of 48	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461754 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.5
DANN	Benign	0.87
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.63
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.21
Sift	Benign	0.61	T
Sift4G	Benign	1.0	T
Polyphen		0.010	B
Vest4		0.091
MutPred		0.41		Loss of glycosylation at P1342 (P = 0.1471)
MVP		0.34
MPC		0.15
ClinPred		0.039	T
GERP RS		-8.9
Varity_R		0.14
gMVP		0.054
Mutation Taster		=89/11	polymorphism

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: rs16823077; hg19: chr2-227892658;