chr10-28534015-G-T

Variant names:

• chr10-28534015-G-T
• rs1366431669
• NM_016628.5:c.59G>T

Variant summary

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

The NM_016628.5(WAC):​c.59G>T​(p.Gly20Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,260 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G20R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WAC NM_016628.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016628.5. 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
	WAC	NM_016628.5	MANE Select	c.59G>T	p.Gly20Val	missense	Exon 2 of 14	NP_057712.2
	WAC	NM_100486.4		c.59G>T	p.Gly20Val	missense	Exon 2 of 13	NP_567823.1	Q9BTA9-5
	WAC	NM_100264.3		c.-77G>T		5_prime_UTR	Exon 2 of 14	NP_567822.1	Q9BTA9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAC	ENST00000354911.9	TSL:1 MANE Select	c.59G>T	p.Gly20Val	missense	Exon 2 of 14	ENSP00000346986.4	Q9BTA9-1
	WAC	ENST00000651885.1		c.59G>T	p.Gly20Val	missense	Exon 2 of 5	ENSP00000498678.1	A0A494C0S5
	WAC	ENST00000375664.8	TSL:1	c.-77G>T		5_prime_UTR	Exon 2 of 14	ENSP00000364816.3	Q9BTA9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449260 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721062

⚠️ 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: 31426

American (AMR) AF: 0.00 AC: 0 AN: 43680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25548

East Asian (EAS) AF: 0.00 AC: 0 AN: 37930

South Asian (SAS) AF: 0.00 AC: 0 AN: 85712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106264

Other (OTH) AF: 0.00 AC: 0 AN: 59826

⚠️ 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	0.14
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.80
MutPred		0.15		Loss of catalytic residue at G20 (P = 0.0444)
MVP		0.17
MPC		0.87
ClinPred		0.79	D
GERP RS		4.9
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.51
gMVP		0.18
Mutation Taster		=79/21	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: rs1366431669; hg19: chr10-28822944;