11-1557003-C-T

Position:

• chr11-1557003-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004420.3(DUSP8):​c.1393G>A​(p.Ala465Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000383 in 1,019,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: DUSP8 NM_004420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

Genes affected

DUSP8 (HGNC:3074): (dual specificity phosphatase 8) The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which is associated with cellular proliferation and differentiation. Different members of the family of dual specificity phosphatases show distinct substrate specificities for various MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. This gene product inactivates SAPK/JNK and p38, is expressed predominantly in the adult brain, heart, and skeletal muscle, is localized in the cytoplasm, and is induced by nerve growth factor and insulin. An intronless pseudogene for DUSP8 is present on chromosome 10q11.2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08404863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP8	NM_004420.3	c.1393G>A	p.Ala465Thr	missense_variant	7/7	ENST00000397374.8	NP_004411.2
DUSP8	XM_011519932.3	c.1393G>A	p.Ala465Thr	missense_variant	7/7		XP_011518234.1
DUSP8	XM_011519933.3	c.1393G>A	p.Ala465Thr	missense_variant	7/7		XP_011518235.1
DUSP8	XM_047426513.1	c.1351G>A	p.Ala451Thr	missense_variant	7/7		XP_047282469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP8	ENST00000397374.8	c.1393G>A	p.Ala465Thr	missense_variant	7/7	1	NM_004420.3	ENSP00000380530.3
DUSP8	ENST00000331588.4	c.1393G>A	p.Ala465Thr	missense_variant	6/6	1		ENSP00000329539.4

Frequencies

GnomAD3 genomes AF: 0.0000818 AC: 12 AN: 146652 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000309 AC: 27 AN: 872598 Hom.: 0 Cov.: 33 AF XY: 0.0000295 AC XY: 12 AN XY: 407298

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: 0.00102

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000761

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000818 AC: 12 AN: 146760 Hom.: 0 Cov.: 32 AF XY: 0.000126 AC XY: 9 AN XY: 71434

Gnomad4 AFR AF: 0.0000733

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

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

Jan 24, 2024

The c.1393G>A (p.A465T) alteration is located in exon 7 (coding exon 6) of the DUSP8 gene. This alteration results from a G to A substitution at nucleotide position 1393, causing the alanine (A) at amino acid position 465 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	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.083	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.090
Sift	Benign	0.60	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.33	B;B
Vest4		0.11
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.35
MPC		1.0
ClinPred		0.20	T
GERP RS		2.7
Varity_R		0.036
gMVP		0.42

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: rs979486067; hg19: chr11-1578233;