rs864321690

Variant names:

Variant summary

Our verdict is The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5

The NM_016628.5(WAC):c.1721G>A (p.Trp574*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.85). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars).

Frequency

Genomes: not found (cov: 33)

Consequence

WAC
NM_016628.5 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.86

Publications

1 publications found

Variant links:

Genes affected

WAC (HGNC:17327): (WW domain containing adaptor with coiled-coil) The protein encoded by this gene contains a WW domain, which is a protein module found in a wide range of signaling proteins. This domain mediates protein-protein interactions and binds proteins containing short linear peptide motifs that are proline-rich or contain at least one proline. This gene product shares 94% sequence identity with the WAC protein in mouse, however, its exact function is not known. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

WAC Gene-Disease associations (from GenCC):

DeSanto-Shinawi syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
DeSanto-Shinawi syndrome due to WAC point mutation
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Illumina, Orphanet

WAC links:

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new If you want to explore the variant's impact on the transcript NM_016628.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 points.

PVS1

Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 12 of 14) at amino acid 574 of 647, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

PP5

ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_016628.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WAC	NM_016628.5	MANE Select	c.1721G>A	p.Trp574*	stop_gained	Exon 12 of 14	NP_057712.2
WAC	NM_100264.3		c.1586G>A	p.Trp529*	stop_gained	Exon 12 of 14	NP_567822.1	Q9BTA9-2
WAC	NM_100486.4		c.1412G>A	p.Trp471*	stop_gained	Exon 11 of 13	NP_567823.1	Q9BTA9-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WAC	ENST00000354911.9	TSL:1 MANE Select	c.1721G>A	p.Trp574*	stop_gained	Exon 12 of 14	ENSP00000346986.4	Q9BTA9-1
WAC	ENST00000375664.8	TSL:1	c.1586G>A	p.Trp529*	stop_gained	Exon 12 of 14	ENSP00000364816.3	Q9BTA9-2
WAC	ENST00000628285.3	TSL:1	n.*1147G>A		3_prime_UTR	Exon 12 of 14	ENSP00000486994.2	A0A0D9SFY7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes					33
GnomAD4 exome					31
GnomAD4 genome					33

Showing 3 sources

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

DeSanto-Shinawi syndrome due to WAC point mutation (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	41
BayesDel_addAF	Pathogenic	D	0.63
BayesDel_noAF	Pathogenic	-	0.66
CADD	Pathogenic	-	43
DANN	Uncertain	-	1.0
Eigen	Pathogenic	-	1.0
Eigen_PC	Pathogenic	-	0.92
FATHMM_MKL	Pathogenic	D	0.99
GPN-Star LLR	N/A	-	-9.8
GPN-Star score	N/A	-	9.8
Mutation Taster	N/A	disease causing (ClinVar)	0/200
PhyloP100	Pathogenic	-	9.9
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.7

Showing 14 of 14 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.11
Pangolin loss	Benign	- Position offset: 25	0.11
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.010

Showing 3 of 3 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

Publications

Other links and lift over