chr10-28534030-A-G

Variant names:

• chr10-28534030-A-G
• rs1216442144
• ENST00000375664:c.-62A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_100264.3(WAC):​c.-62A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,434,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: WAC NM_100264.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3248968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAC	NM_016628.5	c.74A>G	p.Tyr25Cys	missense_variant	Exon 2 of 14	ENST00000354911.9	NP_057712.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAC	ENST00000428935	c.-62A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 8	2		ENSP00000399706.3
WAC	ENST00000651598	c.-80A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6			ENSP00000498480.1
WAC	ENST00000354911.9	c.74A>G	p.Tyr25Cys	missense_variant	Exon 2 of 14	1	NM_016628.5	ENSP00000346986.4
WAC	ENST00000651885.1	c.74A>G	p.Tyr25Cys	missense_variant	Exon 2 of 5			ENSP00000498678.1
WAC	ENST00000428935	c.-62A>G		5_prime_UTR_variant	Exon 2 of 8	2		ENSP00000399706.3
WAC	ENST00000651598	c.-80A>G		5_prime_UTR_variant	Exon 2 of 6			ENSP00000498480.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1434750 Hom.: 0 Cov.: 31 AF XY: 0.00000420 AC XY: 3 AN XY: 713744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000364

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74A>G (p.Y25C) alteration is located in exon 1 (coding exon 1) of the WAC gene. This alteration results from a A to G substitution at nucleotide position 74, causing the tyrosine (Y) at amino acid position 25 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.073	T;T
Polyphen		0.99	D;P
Vest4		0.64
MutPred		0.29		Gain of catalytic residue at P24 (P = 0.0086);Gain of catalytic residue at P24 (P = 0.0086);
MVP		0.068
MPC		0.87
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.60
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs1216442144; hg19: chr10-28822959;