12-105111180-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015275.3(WASHC4):c.117C>G(p.Thr39=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,604,566 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: WASHC4 NM_015275.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.94

Genes affected

WASHC4 (HGNC:29174): (WASH complex subunit 4) This gene encodes a component of the WASH complex, which functions in the intracellular transport of endosomes. Mutations in this gene have been detected in individuals with autosomal recessive cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-105111180-C-G is Benign according to our data. Variant chr12-105111180-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 714546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.94 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0015 (228/152158) while in subpopulation AFR AF= 0.00518 (215/41528). AF 95% confidence interval is 0.00461. There are 2 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASHC4	NM_015275.3	c.117C>G	p.Thr39=	synonymous_variant	2/33	ENST00000332180.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC4	ENST00000332180.10	c.117C>G	p.Thr39=	synonymous_variant	2/33	1	NM_015275.3	A1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152040 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000305 AC: 76 AN: 249034 Hom.: 0 AF XY: 0.000289 AC XY: 39 AN XY: 135174

Gnomad AFR exome AF: 0.00414

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1452408 Hom.: 0 Cov.: 27 AF XY: 0.000133 AC XY: 96 AN XY: 723196

Gnomad4 AFR exome AF: 0.00571

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152158 Hom.: 2 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74376

Gnomad4 AFR AF: 0.00518

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.00152

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 08, 2018

- -

WASHC4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.6
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs147988679; hg19: chr12-105504958;