7-29834729-C-T

Variant names:

• chr7-29834729-C-T
• rs563114242
• NM_001080529.3:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001080529.3(WIPF3):​c.5C>T​(p.Pro2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000529 in 1,513,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: WIPF3 NM_001080529.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080529.3. 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
	WIPF3	NM_001080529.3	MANE Select	c.5C>T	p.Pro2Leu	missense	Exon 2 of 9	NP_001073998.2	A6NGB9
	WIPF3	NM_001391973.1		c.5C>T	p.Pro2Leu	missense	Exon 2 of 8	NP_001378902.1	A0A0A0MSG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WIPF3	ENST00000242140.10	TSL:5 MANE Select	c.5C>T	p.Pro2Leu	missense	Exon 2 of 9	ENSP00000242140.6	A6NGB9
	WIPF3	ENST00000409123.5	TSL:5	c.5C>T	p.Pro2Leu	missense	Exon 2 of 8	ENSP00000386790.1	A0A0A0MSG0
	WIPF3	ENST00000869766.1		c.5C>T	p.Pro2Leu	missense	Exon 2 of 9	ENSP00000539825.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000857 AC: 1 AN: 116686 AF XY: 0.0000168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000243

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000367 AC: 5 AN: 1361370 Hom.: 0 Cov.: 30 AF XY: 0.00000299 AC XY: 2 AN XY: 667988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30520

American (AMR) AF: 0.00 AC: 0 AN: 32196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22272

East Asian (EAS) AF: 0.0000575 AC: 2 AN: 34768

South Asian (SAS) AF: 0.0000140 AC: 1 AN: 71300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060782

Other (OTH) AF: 0.0000177 AC: 1 AN: 56454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000257297), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.97	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.24		Gain of stability (P = 0.0076)
MVP		0.79
MPC		0.080
ClinPred		0.60	D
GERP RS		5.1
Varity_R		0.32
gMVP		0.23
Mutation Taster		=49/51	disease causing

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: rs563114242; hg19: chr7-29874345;