17-37512810-A-G

Position:

• chr17-37512810-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007026.4(DUSP14):​c.538A>G​(p.Ile180Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,613,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DUSP14 NM_007026.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.254

Genes affected

DUSP14 (HGNC:17007): (dual specificity phosphatase 14) Dual-specificity phosphatases (DUSPs) constitute a large heterogeneous subgroup of the type I cysteine-based protein-tyrosine phosphatase superfamily. DUSPs are characterized by their ability to dephosphorylate both tyrosine and serine/threonine residues. They have been implicated as major modulators of critical signaling pathways. DUSP14 contains the consensus DUSP C-terminal catalytic domain but lacks the N-terminal CH2 domain found in the MKP (mitogen-activated protein kinase phosphatase) class of DUSPs (see MIM 600714) (summary by Patterson et al., 2009 [PubMed 19228121]).[supplied by OMIM, Dec 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030281067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP14	NM_007026.4	c.538A>G	p.Ile180Val	missense_variant	3/3	ENST00000617516.5	NP_008957.1
DUSP14	XM_005256977.4	c.538A>G	p.Ile180Val	missense_variant	3/3		XP_005257034.1
DUSP14	XM_011524234.2	c.538A>G	p.Ile180Val	missense_variant	3/3		XP_011522536.1
DUSP14	XM_047435217.1	c.538A>G	p.Ile180Val	missense_variant	3/3		XP_047291173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP14	ENST00000617516.5	c.538A>G	p.Ile180Val	missense_variant	3/3	1	NM_007026.4	ENSP00000478595.1
DUSP14	ENST00000613659.1	c.538A>G	p.Ile180Val	missense_variant	3/3	2		ENSP00000484091.1
DUSP14	ENST00000614411.1	c.538A>G	p.Ile180Val	missense_variant	2/2	2		ENSP00000477653.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 250670 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135692

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000143 AC: 209 AN: 1461018 Hom.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 107 AN XY: 726712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74354

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000382

EpiControl AF: 0.000593

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

Aug 02, 2022

The c.538A>G (p.I180V) alteration is located in exon 3 (coding exon 1) of the DUSP14 gene. This alteration results from a A to G substitution at nucleotide position 538, causing the isoleucine (I) at amino acid position 180 to be replaced by a valine (V). 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	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.2
DANN	Benign	0.89
DEOGEN2	Benign	0.060	T;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.34	N;N;N
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.043
MVP		0.093
ClinPred		0.016	T
GERP RS		-1.2
Varity_R		0.074
gMVP		0.74

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: rs377598867; hg19: chr17-35872912;