rs770087

chr12-89350996-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001946.4(DUSP6):c.430T>G(p.Ser144Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,605,312 control chromosomes in the GnomAD database, including 33,213 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (5176 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28037 hom.)
• Consequence: DUSP6 NM_001946.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.93

Genes affected

DUSP6 (HGNC:3072): (dual specificity phosphatase 6) 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 ERK2, is expressed in a variety of tissues with the highest levels in heart and pancreas, and unlike most other members of this family, is localized in the cytoplasm. Mutations in this gene have been associated with congenital hypogonadotropic hypogonadism. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00386253).
• BP6: Variant 12-89350996-A-C is Benign according to our data. Variant chr12-89350996-A-C is described in ClinVar as [Benign]. Clinvar id is 1261506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-89350996-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUSP6	NM_001946.4	c.430T>G	p.Ser144Ala	missense_variant	2/3	ENST00000279488.8
DUSP6	NM_022652.4	c.400+644T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUSP6	ENST00000279488.8	c.430T>G	p.Ser144Ala	missense_variant	2/3	1	NM_001946.4	P1
	ENST00000611513.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36809 AN: 151982 Hom.: 5167 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.191 AC: 44941 AN: 235852 Hom.: 4785 AF XY: 0.187 AC XY: 23920 AN XY: 127848

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.0282

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.191 AC: 278099 AN: 1453212 Hom.: 28037 Cov.: 32 AF XY: 0.190 AC XY: 137509 AN XY: 722536

Gnomad4 AFR exome AF: 0.384

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.187

Gnomad4 EAS exome AF: 0.0320

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.242 AC: 36859 AN: 152100 Hom.: 5176 Cov.: 32 AF XY: 0.237 AC XY: 17648 AN XY: 74350

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.239

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.0293

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.224

Alfa AF: 0.199 Hom.: 7294

Bravo AF: 0.255

TwinsUK AF: 0.180 AC: 667

ALSPAC AF: 0.179 AC: 690

ESP6500AA AF: 0.383 AC: 1688

ESP6500EA AF: 0.198 AC: 1706

ExAC AF: 0.184 AC: 22373

Asia WGS AF: 0.123 AC: 431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	This variant is associated with the following publications: (PMID: 22155192) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.29	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.17
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.053	T;T
Polyphen		0.0	B;.
Vest4		0.092
MPC		0.59
ClinPred		0.012	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.17

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: rs770087; hg19: chr12-89744773;