9-124855738-C-T

Variant names:

• chr9-124855738-C-T
• rs528155278
• NM_001045476.3:c.295C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001045476.3(WDR38):​c.295C>T​(p.Arg99Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: WDR38 NM_001045476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06650779).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001045476.3. 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
	WDR38	NM_001045476.3	MANE Select	c.295C>T	p.Arg99Trp	missense	Exon 3 of 9	NP_001038941.1	Q5JTN6
	WDR38	NM_001276374.2		c.295C>T	p.Arg99Trp	missense	Exon 3 of 9	NP_001263303.1	A0A087X0D8
	WDR38	NM_001276375.2		c.262C>T	p.Arg88Trp	missense	Exon 3 of 9	NP_001263304.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR38	ENST00000373574.2	TSL:1 MANE Select	c.295C>T	p.Arg99Trp	missense	Exon 3 of 9	ENSP00000362677.1	Q5JTN6
	WDR38	ENST00000613760.4	TSL:1	c.295C>T	p.Arg99Trp	missense	Exon 3 of 9	ENSP00000483312.1	A0A087X0D8
	WDR38	ENST00000618744.4	TSL:1	c.97-59C>T		intron	N/A	ENSP00000483432.1	A0A087X0J1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 248856 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1460912 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 726802

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.3
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.16
Sift	Benign	0.032	D
Sift4G	Benign	0.18	T
Polyphen		0.0040	B
Vest4		0.19
MutPred		0.45		Gain of methylation at K102 (P = 0.0404)
MVP		0.41
MPC		0.17
ClinPred		0.32	T
GERP RS		3.5
Varity_R		0.13
gMVP		0.31
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs528155278; hg19: chr9-127618017; COSMIC: COSV62161383; COSMIC: COSV62161383;