chr5-172770628-G-A

Position:

• chr5-172770628-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_004417.4(DUSP1):​c.325C>T​(p.Leu109Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000429 in 1,165,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: DUSP1 NM_004417.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

Genes affected

DUSP1 (HGNC:3064): (dual specificity phosphatase 1) The protein encoded by this gene is a phosphatase with dual specificity for tyrosine and threonine. The encoded protein can dephosphorylate MAP kinase MAPK1/ERK2, which results in its involvement in several cellular processes. This protein appears to play an important role in the human cellular response to environmental stress as well as in the negative regulation of cellular proliferation. Finally, the encoded protein can make some solid tumors resistant to both chemotherapy and radiotherapy, making it a target for cancer therapy. [provided by RefSeq, Aug 2017]

ENSG00000253736 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP1	NM_004417.4	c.325C>T	p.Leu109Phe	missense_variant	1/4	ENST00000239223.4	NP_004408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP1	ENST00000239223.4	c.325C>T	p.Leu109Phe	missense_variant	1/4	1	NM_004417.4	ENSP00000239223.3
ENSG00000253736	ENST00000523005.1	n.70-6864G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000429 AC: 5 AN: 1165986 Hom.: 0 Cov.: 31 AF XY: 0.00000536 AC XY: 3 AN XY: 560070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000171

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: 0.00000205

Gnomad4 OTH exome AF: 0.0000210

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000378

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

Nov 14, 2023

The c.325C>T (p.L109F) alteration is located in exon 1 (coding exon 1) of the DUSP1 gene. This alteration results from a C to T substitution at nucleotide position 325, causing the leucine (L) at amino acid position 109 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	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.041	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.41
Sift	Benign	0.046	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.30
MutPred		0.70		Gain of catalytic residue at L109 (P = 0.0064);
MVP		0.84
MPC		1.6
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.62
gMVP		0.71

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: rs923998270; hg19: chr5-172197631;