chr9-124853589-C-A

Variant names:

• chr9-124853589-C-A
• rs1453668952
• NM_001045476.3:c.58C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001045476.3(WDR38):​c.58C>A​(p.His20Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000894 in 1,117,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H20Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: WDR38 NM_001045476.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 0 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

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.58C>A	p.His20Asn	missense	Exon 1 of 9	NP_001038941.1	Q5JTN6
	WDR38	NM_001276374.2		c.58C>A	p.His20Asn	missense	Exon 1 of 9	NP_001263303.1	A0A087X0D8
	WDR38	NM_001276375.2		c.58C>A	p.His20Asn	missense	Exon 1 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.58C>A	p.His20Asn	missense	Exon 1 of 9	ENSP00000362677.1	Q5JTN6
	WDR38	ENST00000613760.4	TSL:1	c.58C>A	p.His20Asn	missense	Exon 1 of 9	ENSP00000483312.1	A0A087X0D8
	WDR38	ENST00000618744.4	TSL:1	c.-37C>A		5_prime_UTR	Exon 1 of 8	ENSP00000483432.1	A0A087X0J1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.94e-7 AC: 1 AN: 1117992 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 530168

African (AFR) AF: 0.00 AC: 0 AN: 24528

American (AMR) AF: 0.00 AC: 0 AN: 9954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14522

East Asian (EAS) AF: 0.00 AC: 0 AN: 29152

South Asian (SAS) AF: 0.00 AC: 0 AN: 21256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4482

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 932598

Other (OTH) AF: 0.00 AC: 0 AN: 44860

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.4
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.85		Gain of MoRF binding (P = 0.0994)
MVP		0.79
MPC		0.72
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		0.014	Neutral
Varity_R		0.80
gMVP		0.17
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1453668952; hg19: chr9-127615868;