NM_007240.3:c.340C>G

Variant names:

• chr1-161750141-C-G
• NM_007240.3:c.340C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007240.3(DUSP12):​c.340C>G​(p.His114Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DUSP12 NM_007240.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26
• Publications: 0 publications found

Genes affected

DUSP12 (HGNC:3067): (dual specificity phosphatase 12) 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 is 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 is the human ortholog of the Saccharomyces cerevisiae YVH1 protein tyrosine phosphatase. It is localized predominantly in the nucleus, and is novel in that it contains, and is regulated by a zinc finger domain. [provided by RefSeq, Jul 2008]

ATF6-DT (HGNC:55826): (ATF6 divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007240.3. 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
	DUSP12	NM_007240.3	MANE Select	c.340C>G	p.His114Asp	missense	Exon 1 of 6	NP_009171.1	Q9UNI6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP12	ENST00000367943.5	TSL:1 MANE Select	c.340C>G	p.His114Asp	missense	Exon 1 of 6	ENSP00000356920.4	Q9UNI6
	DUSP12	ENST00000931531.1		c.340C>G	p.His114Asp	missense	Exon 1 of 7	ENSP00000601590.1
	DUSP12	ENST00000954828.1		c.340C>G	p.His114Asp	missense	Exon 1 of 7	ENSP00000624887.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458864 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725796

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 43898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111094

Other (OTH) AF: 0.0000166 AC: 1 AN: 60280

GnomAD4 genome Cov.: 32

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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.81		Loss of MoRF binding (P = 0.2549)
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

hg19: chr1-161719931;