chr10-110498239-C-A

Variant names:

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

Variant summary

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

The NM_004419.4(DUSP5):​c.118C>A​(p.Arg40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,356,904 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DUSP5 NM_004419.4 missense
• Clinical Significance: Not reported in ClinVar
• 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>A	p.Arg40Ser	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>A	p.Arg40Ser	missense	Exon 1 of 4	ENSP00000358596.3	Q16690
	DUSP5	ENST00000925260.1		c.118C>A	p.Arg40Ser	missense	Exon 1 of 4	ENSP00000595319.1
	DUSP5	ENST00000895745.1		c.118C>A	p.Arg40Ser	missense	Exon 1 of 2	ENSP00000565804.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000107 AC: 2 AN: 187168 AF XY: 0.00000947

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000760

Gnomad NFE exome AF: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1356904 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 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: 0.0000256 AC: 1 AN: 39096

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

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1059398

Other (OTH) AF: 0.00 AC: 0 AN: 54712

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00380082), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000845 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	0.0074	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.16	T
Sift4G	Benign	0.35	T
Polyphen		0.98	D
Vest4		0.39
MutPred		0.53		Loss of MoRF binding (P = 0.0152)
MVP		0.62
MPC		1.2
ClinPred		0.65	D
GERP RS		4.9
PromoterAI		0.015	Neutral
Varity_R		0.52
gMVP		0.64
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;