11-1556982-G-A

Position:

• chr11-1556982-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004420.3(DUSP8):​c.1414C>T​(p.Leu472Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000112 in 890,904 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: DUSP8 NM_004420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28092918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUSP8	NM_004420.3	c.1414C>T	p.Leu472Phe	missense_variant	7/7	ENST00000397374.8
DUSP8	XM_011519932.3	c.1414C>T	p.Leu472Phe	missense_variant	7/7
DUSP8	XM_011519933.3	c.1414C>T	p.Leu472Phe	missense_variant	7/7
DUSP8	XM_047426513.1	c.1372C>T	p.Leu458Phe	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUSP8	ENST00000397374.8	c.1414C>T	p.Leu472Phe	missense_variant	7/7	1	NM_004420.3	P1
DUSP8	ENST00000331588.4	c.1414C>T	p.Leu472Phe	missense_variant	6/6	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000112 AC: 1 AN: 890904 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 419088

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000125

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 23, 2023

The c.1414C>T (p.L472F) alteration is located in exon 7 (coding exon 6) of the DUSP8 gene. This alteration results from a C to T substitution at nucleotide position 1414, causing the leucine (L) at amino acid position 472 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.56	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.098
Sift	Benign	0.72	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.97	D;D
Vest4		0.080
MutPred		0.42		Loss of catalytic residue at L472 (P = 0.1097);Loss of catalytic residue at L472 (P = 0.1097);
MVP		0.53
MPC		1.9
ClinPred		0.53	D
GERP RS		2.9
Varity_R		0.093
gMVP		0.40

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: rs1025856895; hg19: chr11-1578212;