rs12767429

Variant names:

• chr10-28533444-A-C
• rs12767429
• NM_016628.5:c.-136A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016628.5(WAC):​c.-136A>C 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 1 in 278,812 control chromosomes in the GnomAD database, including 139,403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (74747 hom., cov: 29)
  • Exomes 𝑓: 1.0 (64656 hom.)
• Consequence: WAC NM_016628.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 5 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, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-28533444-A-C is Benign according to our data. Variant chr10-28533444-A-C is described in ClinVar as Benign. ClinVar VariationId is 1271155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.-136A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_057712.2
	WAC	NM_016628.5	MANE Select	c.-136A>C		5_prime_UTR	Exon 1 of 14	NP_057712.2
	WAC	NM_100486.4		c.-136A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	NP_567823.1	Q9BTA9-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAC	ENST00000354911.9	TSL:1 MANE Select	c.-136A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000346986.4	Q9BTA9-1
	WAC	ENST00000354911.9	TSL:1 MANE Select	c.-136A>C		5_prime_UTR	Exon 1 of 14	ENSP00000346986.4	Q9BTA9-1
	WAC	ENST00000375664.8	TSL:1	c.-95+437A>C		intron	N/A	ENSP00000364816.3	Q9BTA9-2

Frequencies

GnomAD3 genomes AF: 1.00 AC: 149386 AN: 149386 Hom.: 74693 Cov.: 29

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD4 exome AF: 1.00 AC: 129314 AN: 129318 Hom.: 64656 Cov.: 5 AF XY: 1.00 AC XY: 63874 AN XY: 63874

African (AFR) AF: 1.00 AC: 2168 AN: 2168

American (AMR) AF: 1.00 AC: 218 AN: 218

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 830 AN: 830

East Asian (EAS) AF: 1.00 AC: 628 AN: 628

South Asian (SAS) AF: 1.00 AC: 3288 AN: 3288

European-Finnish (FIN) AF: 1.00 AC: 2738 AN: 2738

Middle Eastern (MID) AF: 1.00 AC: 274 AN: 274

European-Non Finnish (NFE) AF: 1.00 AC: 115002 AN: 115006

Other (OTH) AF: 1.00 AC: 4168 AN: 4168

GnomAD4 genome AF: 1.00 AC: 149494 AN: 149494 Hom.: 74747 Cov.: 29 AF XY: 1.00 AC XY: 72914 AN XY: 72914

African (AFR) AF: 1.00 AC: 41228 AN: 41228

American (AMR) AF: 1.00 AC: 15084 AN: 15084

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3432 AN: 3432

East Asian (EAS) AF: 1.00 AC: 5020 AN: 5020

South Asian (SAS) AF: 1.00 AC: 4812 AN: 4812

European-Finnish (FIN) AF: 1.00 AC: 9566 AN: 9566

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 67068 AN: 67068

Other (OTH) AF: 1.00 AC: 2080 AN: 2080

Alfa AF: 1.00 Hom.: 8743

Bravo AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.89
PhyloP100		1.0
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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: rs12767429; hg19: chr10-28822373;