rs864321690

Variant names:

• chr10-28616337-G-A
• rs864321690
• NM_016628.5:c.1721G>A
• WAC p.Trp574*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.86
• Publications: 1 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		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.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		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

Sel.	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	Prot: NP_057712.2
	WAC NM_100264.3		c.1586G>A p.Trp529*	stop_gained	Exon 12 of 14	Prot: NP_567822.1 UniProt:
	WAC NM_100486.4		c.1412G>A p.Trp471*	stop_gained	Exon 11 of 13	Prot: NP_567823.1 UniProt:

WAC NM_016628.5

MANE Select

HGVSc / HGVSpc.1721G>Ap.Trp574*

Exon rankExon 12 of 14

stop_gained

Prot: NP_057712.2

WAC NM_100264.3

HGVSc / HGVSpc.1586G>Ap.Trp529*

Exon rankExon 12 of 14

stop_gained

Prot: NP_567822.1UniProt: Q9BTA9-2

WAC NM_100486.4

HGVSc / HGVSpc.1412G>Ap.Trp471*

Exon rankExon 11 of 13

stop_gained

Prot: NP_567823.1UniProt: Q9BTA9-5

Ensembl Transcripts

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

WAC ENST00000354911.9

TSL:1MANE Select

HGVSc / HGVSpc.1721G>Ap.Trp574*

Exon rankExon 12 of 14

stop_gained

Prot: ENSP00000346986.4UniProt: Q9BTA9-1

WAC ENST00000375664.8

TSL:1

HGVSc / HGVSpc.1586G>Ap.Trp529*

Exon rankExon 12 of 14

stop_gained

Prot: ENSP00000364816.3UniProt: Q9BTA9-2

WAC ENST00000628285.3

TSL:1

HGVSc / HGVSpn.*1147G>A

Exon rankExon 12 of 14

3_prime_UTR

Prot: ENSP00000486994.2UniProt: 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	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	DeSanto-Shinawi syndrome due to WAC point mutation (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	41
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-9.8
GPN-Star score	N/A	9.8
Mutation Taster	N/A	0/200	disease causing (ClinVar)
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 pred.	Score	Prediction
Pangolin (max)	Benign	0.11
Pangolin loss	Benign	0.11	Position offset: 25
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs864321690;

hg19: chr10-28905266;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar