Genetic Variant NM_020212.2:c.834T>G (chr15-89722093-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020212.2(WDR93):c.834T>G(p.Ser278Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,264 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S278S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

WDR93
NM_020212.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.390

Publications

0 publications found

Variant links:

Genes affected

WDR93 (HGNC:26924): (WD repeat domain 93) Predicted to enable oxidoreductase activity, acting on NAD(P)H. Predicted to be involved in electron transport chain. Predicted to be part of mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

WDR93 Gene-Disease associations (from GenCC):

autism spectrum disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

WDR93 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR93	NM_020212.2 link	c.834T>G	p.Ser278Arg	missense_variant	Exon 8 of 17	ENST00000268130.12	NP_064597.1	Q6P2C0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WDR93	ENST00000268130.12 link	c.834T>G	p.Ser278Arg	missense_variant	Exon 8 of 17	1	NM_020212.2	ENSP00000268130.7	Q6P2C0-1
WDR93	ENST00000560294.5 link	c.834T>G	p.Ser278Arg	missense_variant	Exon 8 of 17	2		ENSP00000453971.1	Q6P2C0-2
WDR93	ENST00000444934.3 link	n.340T>G		non_coding_transcript_exon_variant	Exon 2 of 11	2
WDR93	ENST00000557825.5 link	n.223T>G		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724816

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33282

American (AMR)

AF:

0.00

AC:

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.00

AC:

AN:

85070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110586

Other (OTH)

AF:

0.00

AC:

AN:

60230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

0.39

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.086

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.93

P;P

Vest4

0.70

MutPred

0.41

Loss of ubiquitination at K276 (P = 0.0413);Loss of ubiquitination at K276 (P = 0.0413);

MVP

0.061

MPC

0.36

ClinPred

0.96

GERP RS

-2.1

Varity_R

0.31

gMVP

0.70

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over