7-29884143-C-A

Position:

• chr7-29884143-C-A

Variant summary

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

The NM_001080529.3(WIPF3):​c.649C>A​(p.Pro217Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,374,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: WIPF3 NM_001080529.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.566

Genes affected

WIPF3 (HGNC:22004): (WAS/WASL interacting protein family member 3) Predicted to enable SH3 domain binding activity and actin binding activity. Predicted to be involved in actin filament-based movement. Predicted to be located in cytosol. Predicted to be active in actin filament. [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=0.22286615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WIPF3	NM_001080529.3	c.649C>A	p.Pro217Thr	missense_variant	5/9	ENST00000242140.10	NP_001073998.2
WIPF3	NM_001391973.1	c.649C>A	p.Pro217Thr	missense_variant	5/8		NP_001378902.1
WIPF3	XM_017012522.2	c.616C>A	p.Pro206Thr	missense_variant	4/8		XP_016868011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WIPF3	ENST00000242140.10	c.649C>A	p.Pro217Thr	missense_variant	5/9	5	NM_001080529.3	ENSP00000242140.6
WIPF3	ENST00000409123.5	c.649C>A	p.Pro217Thr	missense_variant	5/8	5		ENSP00000386790.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000124 AC: 17 AN: 1374404 Hom.: 0 Cov.: 36 AF XY: 0.0000104 AC XY: 7 AN XY: 676152

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: 0.0000262

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.0000103

Gnomad4 OTH exome AF: 0.0000528

GnomAD4 genome Cov.: 23

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 21, 2023

The c.649C>A (p.P217T) alteration is located in exon 5 (coding exon 4) of the WIPF3 gene. This alteration results from a C to A substitution at nucleotide position 649, causing the proline (P) at amino acid position 217 to be replaced by a threonine (T). 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	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.30	.;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.48	T;T;.
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.44	.;B;B
Vest4		0.18
MutPred		0.24		Gain of phosphorylation at P217 (P = 0.009);Gain of phosphorylation at P217 (P = 0.009);Gain of phosphorylation at P217 (P = 0.009);
MVP		0.33
MPC		0.42
ClinPred		0.48	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.31

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: rs780259388; hg19: chr7-29923759;