10-28533659-G-GGGC

Variant names:

• chr10-28533659-G-GGGC
• rs749860033
• NM_016628.5:c.41+48_41+50dupCGG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_016628.5(WAC):​c.41+48_41+50dupCGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,540,618 control chromosomes in the GnomAD database, including 47 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (20 hom.)
• Consequence: WAC NM_016628.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 10-28533659-G-GGGC is Benign according to our data. Variant chr10-28533659-G-GGGC is described in ClinVar as Likely_benign. ClinVar VariationId is 1335861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00908 (1371/150948) while in subpopulation AFR AF = 0.0315 (1300/41216). AF 95% confidence interval is 0.0301. There are 27 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1371 AD gene.

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.41+48_41+50dupCGG		intron	N/A	NP_057712.2
	WAC	NM_100264.3		c.-94-330_-94-328dupCGG		intron	N/A	NP_567822.1	Q9BTA9-2
	WAC	NM_100486.4		c.41+48_41+50dupCGG		intron	N/A	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.41+39_41+40insGGC		intron	N/A	ENSP00000346986.4	Q9BTA9-1
	WAC	ENST00000375664.8	TSL:1	c.-94-339_-94-338insGGC		intron	N/A	ENSP00000364816.3	Q9BTA9-2
	WAC	ENST00000428935.6	TSL:2	c.-94-339_-94-338insGGC		intron	N/A	ENSP00000399706.3	A0A0A0MSR1

Frequencies

GnomAD3 genomes AF: 0.00908 AC: 1370 AN: 150838 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00296

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000237

Gnomad OTH AF: 0.00482

GnomAD2 exomes AF: 0.00197 AC: 302 AN: 152914 AF XY: 0.00162

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000947

GnomAD4 exome AF: 0.000925 AC: 1285 AN: 1389670 Hom.: 20 Cov.: 29 AF XY: 0.000796 AC XY: 547 AN XY: 686904

African (AFR) AF: 0.0315 AC: 959 AN: 30468

American (AMR) AF: 0.00183 AC: 66 AN: 36022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24908

East Asian (EAS) AF: 0.00 AC: 0 AN: 35194

South Asian (SAS) AF: 0.0000635 AC: 5 AN: 78800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47758

Middle Eastern (MID) AF: 0.000496 AC: 2 AN: 4030

European-Non Finnish (NFE) AF: 0.000131 AC: 141 AN: 1074918

Other (OTH) AF: 0.00195 AC: 112 AN: 57572

GnomAD4 genome AF: 0.00908 AC: 1371 AN: 150948 Hom.: 27 Cov.: 32 AF XY: 0.00872 AC XY: 643 AN XY: 73748

African (AFR) AF: 0.0315 AC: 1300 AN: 41216

American (AMR) AF: 0.00295 AC: 45 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4990

South Asian (SAS) AF: 0.00 AC: 0 AN: 4742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000237 AC: 16 AN: 67524

Other (OTH) AF: 0.00477 AC: 10 AN: 2098

Alfa AF: 0.000685 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

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.

Other links and lift over

dbSNP: rs749860033; hg19: chr10-28822588;