chr22-30663634-C-A

Variant names:

• chr22-30663634-C-A
• rs775433384
• NM_152511.5:c.370G>T

Variant summary

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

The NM_152511.5(DUSP18):​c.370G>T​(p.Ala124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. A124T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DUSP18 NM_152511.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• Publications: 0 publications found

Genes affected

DUSP18 (HGNC:18484): (dual specificity phosphatase 18) Dual-specificity phosphatases (DUSPs) constitute a large heterogeneous subgroup of the type I cysteine-based protein-tyrosine phosphatase superfamily. DUSPs are characterized by their ability to dephosphorylate both tyrosine and serine/threonine residues. They have been implicated as major modulators of critical signaling pathways. DUSP18 contains the consensus DUSP C-terminal catalytic domain but lacks the N-terminal CH2 domain found in the MKP (mitogen-activated protein kinase phosphatase) class of DUSPs (see MIM 600714) (summary by Patterson et al., 2009 [PubMed 19228121]).[supplied by OMIM, Dec 2009]

SLC35E4 (HGNC:17058): (solute carrier family 35 member E4) Predicted to enable antiporter activity. Predicted to be involved in transmembrane transport. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus. [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=0.054546535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152511.5. 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
	DUSP18	NM_152511.5	MANE Select	c.370G>T	p.Ala124Ser	missense	Exon 2 of 2	NP_689724.3
	DUSP18	NM_001304794.2		c.370G>T	p.Ala124Ser	missense	Exon 3 of 3	NP_001291723.1	Q8NEJ0
	DUSP18	NM_001304795.2		c.370G>T	p.Ala124Ser	missense	Exon 2 of 3	NP_001291724.1	Q8NEJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP18	ENST00000334679.4	TSL:1 MANE Select	c.370G>T	p.Ala124Ser	missense	Exon 2 of 2	ENSP00000333917.3	Q8NEJ0
	DUSP18	ENST00000404885.5	TSL:1	c.370G>T	p.Ala124Ser	missense	Exon 2 of 3	ENSP00000385463.1	Q8NEJ0
	DUSP18	ENST00000403268.1	TSL:1	c.260G>T	p.Arg87Leu	missense	Exon 3 of 3	ENSP00000384946.1	F2Z2P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.84
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.017
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.033
Sift	Benign	0.93	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.31		Loss of ubiquitination at K121 (P = 0.121)
MVP		0.43
MPC		0.038
ClinPred		0.41	T
GERP RS		1.6
Varity_R		0.048
gMVP		0.073
Mutation Taster		=90/10	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: rs775433384; hg19: chr22-31059621;