chr19-34482522-C-T

Position:

• chr19-34482522-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080436.2(WTIP):​c.548C>T​(p.Pro183Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000927 in 1,078,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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: -0.762

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16925764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WTIP	NM_001080436.2	c.548C>T	p.Pro183Leu	missense_variant	1/8	ENST00000590071.7
WTIP	XM_011526452.4	c.548C>T	p.Pro183Leu	missense_variant	1/8
WTIP	XM_006723014.5	c.548C>T	p.Pro183Leu	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WTIP	ENST00000590071.7	c.548C>T	p.Pro183Leu	missense_variant	1/8	1	NM_001080436.2	P1
WTIP	ENST00000585928.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 9.27e-7 AC: 1 AN: 1078654 Hom.: 0 Cov.: 75 AF XY: 0.00000195 AC XY: 1 AN XY: 512450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

Asia WGS AF: 0.000291 AC: 1 AN: 3448

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

Oct 30, 2023

The c.548C>T (p.P183L) alteration is located in exon 1 (coding exon 1) of the WTIP gene. This alteration results from a C to T substitution at nucleotide position 548, causing the proline (P) at amino acid position 183 to be replaced by a leucine (L). 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	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.92	D
Sift4G	Uncertain	0.0050	D
Vest4		0.093
MVP		0.42
MPC		1.1
ClinPred		0.15	T
GERP RS		1.9
Varity_R		0.046
gMVP		0.67

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: rs928404384; hg19: chr19-34973427;