10-110498284-G-T

Position:

• chr10-110498284-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004419.4(DUSP5):​c.163G>T​(p.Ala55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,451,112 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: DUSP5 NM_004419.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.56

Genes affected

DUSP5 (HGNC:3071): (dual specificity phosphatase 5) 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 are 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 ERK1, is expressed in a variety of tissues with the highest levels in pancreas and brain, and is localized in the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007921934).
• BP6: Variant 10-110498284-G-T is Benign according to our data. Variant chr10-110498284-G-T is described in ClinVar as [Benign]. Clinvar id is 780891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2072/149612) while in subpopulation AFR AF= 0.0473 (1951/41232). AF 95% confidence interval is 0.0456. There are 49 homozygotes in gnomad4. There are 997 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP5	NM_004419.4	c.163G>T	p.Ala55Ser	missense_variant	1/4	ENST00000369583.4	NP_004410.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP5	ENST00000369583.4	c.163G>T	p.Ala55Ser	missense_variant	1/4	1	NM_004419.4	ENSP00000358596.3

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2066 AN: 149506 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00578

Gnomad ASJ AF: 0.00351

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000896

Gnomad OTH AF: 0.00831

GnomAD3 exomes AF: 0.00281 AC: 475 AN: 168848 Hom.: 10 AF XY: 0.00196 AC XY: 190 AN XY: 96728

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000412

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000507

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00127 AC: 1654 AN: 1301500 Hom.: 38 Cov.: 31 AF XY: 0.00112 AC XY: 724 AN XY: 647156

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.00258

Gnomad4 ASJ exome AF: 0.000988

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000525

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.0138 AC: 2072 AN: 149612 Hom.: 49 Cov.: 32 AF XY: 0.0137 AC XY: 997 AN XY: 73014

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.00571

Gnomad4 ASJ AF: 0.00351

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000896

Gnomad4 OTH AF: 0.00822

Alfa AF: 0.000750 Hom.: 2

ESP6500AA AF: 0.0453 AC: 189

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.00394 AC: 456

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.063
Sift	Benign	0.34	T
Sift4G	Benign	0.44	T
Polyphen		0.12	B
Vest4		0.083
MVP		0.52
MPC		1.1
ClinPred		0.0087	T
GERP RS		4.1
Varity_R		0.17
gMVP		0.25

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: rs74386806; hg19: chr10-112258042; COSMIC: COSV63646909; COSMIC: COSV63646909;