chr7-123684540-A-C

Variant names:

• chr7-123684540-A-C
• rs765077591
• NM_003941.4:c.1497T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003941.4(WASL):​c.1497T>G​(p.Asp499Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,164,192 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: WASL NM_003941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.683
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23072293).

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.1497T>G	p.Asp499Glu	missense	Exon 11 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.1497T>G	p.Asp499Glu	missense	Exon 11 of 11	ENSP00000223023.4	O00401
	WASL	ENST00000924343.1		c.1491T>G	p.Asp497Glu	missense	Exon 11 of 11	ENSP00000594402.1
	WASL	ENST00000924344.1		c.1410T>G	p.Asp470Glu	missense	Exon 10 of 10	ENSP00000594403.1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151042 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000133 AC: 2 AN: 150666 AF XY: 0.0000252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000851

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000474 AC: 48 AN: 1013150 Hom.: 0 Cov.: 14 AF XY: 0.0000505 AC XY: 26 AN XY: 515110

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

African (AFR) AF: 0.0000424 AC: 1 AN: 23596

American (AMR) AF: 0.0000588 AC: 2 AN: 34002

Ashkenazi Jewish (ASJ) AF: 0.0000899 AC: 2 AN: 22254

East Asian (EAS) AF: 0.00 AC: 0 AN: 33224

South Asian (SAS) AF: 0.00 AC: 0 AN: 68698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4842

European-Non Finnish (NFE) AF: 0.0000586 AC: 43 AN: 733980

Other (OTH) AF: 0.00 AC: 0 AN: 44754

⚠️ 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 AF: 0.00000662 AC: 1 AN: 151042 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73728

African (AFR) AF: 0.00 AC: 0 AN: 41198

American (AMR) AF: 0.0000663 AC: 1 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67670

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000139 AC: 1

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	Benign	0.15
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.0082
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.23	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.20	N
PhyloP100		0.68
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.46	T
Polyphen		0.98	D
Vest4		0.13
MutPred		0.12		Gain of helix (P = 0.0854)
MVP		0.68
MPC		0.29
ClinPred		0.35	T
GERP RS		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.28
gMVP		0.018
Mutation Taster		=85/15	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: rs765077591; hg19: chr7-123324594;