chr6-110101644-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_003931.3(WASF1):​c.1466C>G​(p.Ser489Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

WASF1
NM_003931.3 stop_gained

Scores

5
1
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.47
Variant links:
Genes affected
WASF1 (HGNC:12732): (WASP family member 1) The protein encoded by this gene, a member of the Wiskott-Aldrich syndrome protein (WASP)-family, plays a critical role downstream of Rac, a Rho-family small GTPase, in regulating the actin cytoskeleton required for membrane ruffling. It has been shown to associate with an actin nucleation core Arp2/3 complex while enhancing actin polymerization in vitro. Wiskott-Aldrich syndrome is a disease of the immune system, likely due to defects in regulation of actin cytoskeleton. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-110101644-G-C is Pathogenic according to our data. Variant chr6-110101644-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1342385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WASF1NM_003931.3 linkuse as main transcriptc.1466C>G p.Ser489Ter stop_gained 10/11 ENST00000392589.6
WASF1NM_001024934.2 linkuse as main transcriptc.1466C>G p.Ser489Ter stop_gained 9/10
WASF1NM_001024935.2 linkuse as main transcriptc.1466C>G p.Ser489Ter stop_gained 9/10
WASF1NM_001024936.2 linkuse as main transcriptc.1466C>G p.Ser489Ter stop_gained 8/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WASF1ENST00000392589.6 linkuse as main transcriptc.1466C>G p.Ser489Ter stop_gained 10/115 NM_003931.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with absent language and variable seizures Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterMar 05, 2021The de novo c.1466C>G (p.Ser489Ter) variant identified in the WASF1 gene is a single nucleotide variant leading to the premature termination of the protein at amino acid 489/560 (exon 9/10). This variant is absent from gnomAD(v3.1) suggesting it is not a common benign variant in the populations represented in that database. This variant is absent from ClinVar, and to our current knowledge has not been reported in the literature, although several nonsense and frameshift variants downstream of the one identified here have been reported in affected individuals [PMID:29961568]. Given its deleterious nature, absence in population databases, and presence de novo, the c.1466C>G (p.Ser489Ter) variant identified in the WASF1 gene is reported as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A;A;A;A;A
Vest4
0.63
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-110422847; API