7-123696678-G-T

Variant names:

• chr7-123696678-G-T
• rs376787353
• NM_003941.4:c.530C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003941.4(WASL):​c.530C>A​(p.Pro177Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P177L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WASL NM_003941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.63
• Publications: 0 publications found

Genes affected

WASL (HGNC:12735): (WASP like actin nucleation promoting factor) This gene encodes a member of the Wiskott-Aldrich syndrome (WAS) protein family. Wiskott-Aldrich syndrome proteins share similar domain structure, and associate with a variety of signaling molecules to alter the actin cytoskeleton. The encoded protein is highly expressed in neural tissues, and interacts with several proteins involved in cytoskeletal organization, including cell division control protein 42 (CDC42) and the actin-related protein-2/3 (ARP2/3) complex. The encoded protein may be involved in the formation of long actin microspikes, and in neurite extension. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17945412).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003941.4. 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
	WASL	NM_003941.4	MANE Select	c.530C>A	p.Pro177Gln	missense	Exon 6 of 11	NP_003932.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASL	ENST00000223023.5	TSL:1 MANE Select	c.530C>A	p.Pro177Gln	missense	Exon 6 of 11	ENSP00000223023.4	O00401
	WASL	ENST00000924343.1		c.530C>A	p.Pro177Gln	missense	Exon 6 of 11	ENSP00000594402.1
	WASL	ENST00000924344.1		c.443C>A	p.Pro148Gln	missense	Exon 5 of 10	ENSP00000594403.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451624 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722054

⚠️ 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: 33060

American (AMR) AF: 0.00 AC: 0 AN: 43718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38952

South Asian (SAS) AF: 0.00 AC: 0 AN: 84398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106828

Other (OTH) AF: 0.00 AC: 0 AN: 59920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.18	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	0.75	N
PhyloP100		5.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.36
Sift	Benign	0.18	T
Sift4G	Benign	0.52	T
Polyphen		0.037	B
Vest4		0.28
MutPred		0.24		Gain of MoRF binding (P = 0.0341)
MVP		0.34
MPC		0.39
ClinPred		0.33	T
GERP RS		6.0
Varity_R		0.087
gMVP		0.31
Mutation Taster		=77/23	polymorphism

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: rs376787353; hg19: chr7-123336732;