Genetic Variant NM_007240.3:c.172A>C (chr1-161749973-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007240.3(DUSP12):c.172A>C(p.Thr58Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. T58A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DUSP12
NM_007240.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.768

Publications

0 publications found

Variant links:

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]

DUSP12 links:

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

ATF6-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

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.172A>C	p.Thr58Pro	missense	Exon 1 of 6	NP_009171.1	Q9UNI6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DUSP12	ENST00000367943.5	TSL:1 MANE Select	c.172A>C	p.Thr58Pro	missense	Exon 1 of 6	ENSP00000356920.4	Q9UNI6
DUSP12	ENST00000931531.1		c.172A>C	p.Thr58Pro	missense	Exon 1 of 7	ENSP00000601590.1
DUSP12	ENST00000954828.1		c.172A>C	p.Thr58Pro	missense	Exon 1 of 7	ENSP00000624887.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111928

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.4

PhyloP100

0.77

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0090

Polyphen

0.96

Vest4

0.79

MutPred

0.69

Loss of phosphorylation at T58 (P = 0.0522)

MVP

0.93

MPC

1.1

ClinPred

0.99

GERP RS

3.7

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.98

gMVP

0.89

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over