22-30663517-T-C

Position:

• chr22-30663517-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152511.5(DUSP18):​c.487A>G​(p.Thr163Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,614,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: DUSP18 NM_152511.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032183647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUSP18	NM_152511.5	c.487A>G	p.Thr163Ala	missense_variant	2/2	ENST00000334679.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUSP18	ENST00000334679.4	c.487A>G	p.Thr163Ala	missense_variant	2/2	1	NM_152511.5	P1

Frequencies

GnomAD3 genomes AF: 0.000709 AC: 108 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000668 AC: 168 AN: 251492 Hom.: 0 AF XY: 0.000714 AC XY: 97 AN XY: 135920

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00117 AC: 1707 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00118 AC XY: 858 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74504

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000805

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000830

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

Oct 18, 2021

The c.487A>G (p.T163A) alteration is located in exon 2 (coding exon 1) of the DUSP18 gene. This alteration results from a A to G substitution at nucleotide position 487, causing the threonine (T) at amino acid position 163 to be replaced by an alanine (A). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T;T;.
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.028	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.5	M;M;M;.
MutationTaster	Benign	0.82	D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.47	P;P;P;.
Vest4		0.26
MVP		0.70
MPC		0.048
ClinPred		0.046	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147361219; hg19: chr22-31059504;