6-159755210-G-A

Position:

• chr6-159755210-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001270531.2(WTAP):​c.790G>A​(p.Glu264Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E264G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WTAP NM_001270531.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

Genes affected

WTAP (HGNC:16846): (WT1 associated protein) The Wilms tumor suppressor gene WT1 appears to play a role in both transcriptional and posttranscriptional regulation of certain cellular genes. This gene encodes a WT1-associating protein, which is a ubiquitously expressed nuclear protein. Like WT1 protein, this protein is localized throughout the nucleoplasm as well as in speckles and partially colocalizes with splicing factors. Alternative splicing of this gene results in several transcript variants encoding three different isoforms. [provided by RefSeq, Jul 2012]

SOD2 (HGNC:11180): (superoxide dismutase 2) This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 1. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3225676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WTAP	NM_001270531.2	c.790G>A	p.Glu264Lys	missense_variant	8/8	ENST00000621533.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WTAP	ENST00000621533.5	c.790G>A	p.Glu264Lys	missense_variant	8/8	2	NM_001270531.2	P1
WTAP	ENST00000358372.8	c.790G>A	p.Glu264Lys	missense_variant	8/8	1		P1
SOD2	ENST00000546087.5	c.-336+5827C>T		intron_variant		2
WTAP	ENST00000650096.1	c.*1975G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2022

The c.790G>A (p.E264K) alteration is located in exon 8 (coding exon 7) of the WTAP gene. This alteration results from a G to A substitution at nucleotide position 790, causing the glutamic acid (E) at amino acid position 264 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.97	N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	D;.
Sift4G	Benign	0.81	T;T
Polyphen		1.0	D;D
Vest4		0.33
MutPred		0.17		Gain of ubiquitination at E264 (P = 9e-04);Gain of ubiquitination at E264 (P = 9e-04);
MVP		0.17
MPC		1.1
ClinPred		0.75	D
GERP RS		6.2
Varity_R		0.33
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-160176242;