19-34482549-A-G

Position:

• chr19-34482549-A-G

Variant summary

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

The NM_001080436.2(WTIP):​c.575A>G​(p.Glu192Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000928 in 1,077,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: WTIP NM_001080436.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

WTIP (HGNC:20964): (WT1 interacting protein) Predicted to enable transcription corepressor activity. Involved in several processes, including negative regulation of hippo signaling; positive regulation of gene silencing by miRNA; and response to hypoxia. Acts upstream of or within gene silencing by miRNA. Located in P-body. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2929985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WTIP	NM_001080436.2	c.575A>G	p.Glu192Gly	missense_variant	1/8	ENST00000590071.7
WTIP	XM_011526452.4	c.575A>G	p.Glu192Gly	missense_variant	1/8
WTIP	XM_006723014.5	c.575A>G	p.Glu192Gly	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WTIP	ENST00000590071.7	c.575A>G	p.Glu192Gly	missense_variant	1/8	1	NM_001080436.2	P1
WTIP	ENST00000585928.1	c.23A>G	p.Glu8Gly	missense_variant	1/8	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 9.28e-7 AC: 1 AN: 1077250 Hom.: 0 Cov.: 75 AF XY: 0.00 AC XY: 0 AN XY: 510150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000383

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

May 30, 2023

The c.575A>G (p.E192G) alteration is located in exon 1 (coding exon 1) of the WTIP gene. This alteration results from a A to G substitution at nucleotide position 575, causing the glutamic acid (E) at amino acid position 192 to be replaced by a glycine (G). 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	0.084
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.97	D;D
PrimateAI	Pathogenic	0.94	D
Sift4G	Uncertain	0.034	D
Vest4		0.22
MVP		0.49
MPC		1.0
ClinPred		0.95	D
GERP RS		3.1
Varity_R		0.28
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs1220178677; hg19: chr19-34973454;