9-124855914-G-A

Position:

• chr9-124855914-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001045476.3(WDR38):​c.361G>A​(p.Ala121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDR38 NM_001045476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

Genes affected

WDR38 (HGNC:23745): (WD repeat domain 38) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR38	NM_001045476.3	c.361G>A	p.Ala121Thr	missense_variant	4/9	ENST00000373574.2	NP_001038941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR38	ENST00000373574.2	c.361G>A	p.Ala121Thr	missense_variant	4/9	1	NM_001045476.3	ENSP00000362677.1
WDR38	ENST00000613760.4	c.361G>A	p.Ala121Thr	missense_variant	4/9	1		ENSP00000483312.1
WDR38	ENST00000618744.4	c.214G>A	p.Ala72Thr	missense_variant	3/8	1		ENSP00000483432.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727168

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.361G>A (p.A121T) alteration is located in exon 4 (coding exon 4) of the WDR38 gene. This alteration results from a G to A substitution at nucleotide position 361, causing the alanine (A) at amino acid position 121 to be replaced by a threonine (T). 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	0.29
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	.;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.5	.;.;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	.;.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.010	.;.;D
Sift4G	Uncertain	0.044	D;T;D
Polyphen		0.94	.;.;P
Vest4		0.58
MutPred		0.78		Gain of phosphorylation at A121 (P = 0.0467);.;Gain of phosphorylation at A121 (P = 0.0467);
MVP		0.82
MPC		0.65
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.18
gMVP		0.30

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: rs778908776; hg19: chr9-127618193;