10-110498239-C-T

Variant names:

• chr10-110498239-C-T
• rs769352051
• NM_004419.4:c.118C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004419.4(DUSP5):​c.118C>T​(p.Arg40Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,356,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DUSP5 NM_004419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004419.4. 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
	DUSP5	NM_004419.4	MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 1 of 4	NP_004410.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP5	ENST00000369583.4	TSL:1 MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 1 of 4	ENSP00000358596.3	Q16690
	DUSP5	ENST00000925260.1		c.118C>T	p.Arg40Cys	missense	Exon 1 of 4	ENSP00000595319.1
	DUSP5	ENST00000895745.1		c.118C>T	p.Arg40Cys	missense	Exon 1 of 2	ENSP00000565804.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149624 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1356904 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 675990

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27866

American (AMR) AF: 0.00 AC: 0 AN: 37378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22808

East Asian (EAS) AF: 0.00 AC: 0 AN: 30224

South Asian (SAS) AF: 0.00 AC: 0 AN: 80034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5388

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059398

Other (OTH) AF: 0.0000183 AC: 1 AN: 54712

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 149624 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72976

African (AFR) AF: 0.00 AC: 0 AN: 41156

American (AMR) AF: 0.00 AC: 0 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67042

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.0000936 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.98	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Benign	0.066	T
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.51		Loss of MoRF binding (P = 0.0054)
MVP		0.62
MPC		1.5
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.070	Neutral
Varity_R		0.39
gMVP		0.67
Mutation Taster		=55/45	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: rs769352051; hg19: chr10-112257997;