12-89348954-T-C

Position:

• chr12-89348954-T-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.*300A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 314,128 control chromosomes in the GnomAD database, including 10,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7080 hom., cov: 33)
  • Exomes 𝑓: 0.19 (3695 hom.)
• Consequence: DUSP6 NM_001946.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 12-89348954-T-C is Benign according to our data. Variant chr12-89348954-T-C is described in ClinVar as [Benign]. Clinvar id is 1268548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP6	NM_001946.4	c.*300A>G		3_prime_UTR_variant	3/3	ENST00000279488.8	NP_001937.2
DUSP6	NM_022652.4	c.*300A>G		3_prime_UTR_variant	2/2		NP_073143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP6	ENST00000279488.8	c.*300A>G		3_prime_UTR_variant	3/3	1	NM_001946.4	ENSP00000279488	P1
DUSP6	ENST00000308385.6	c.*300A>G		3_prime_UTR_variant	2/2	1		ENSP00000307835

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41302 AN: 152040 Hom.: 7064 Cov.: 33

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.248

GnomAD4 exome AF: 0.191 AC: 30966 AN: 161970 Hom.: 3695 Cov.: 0 AF XY: 0.189 AC XY: 15762 AN XY: 83518

Gnomad4 AFR exome AF: 0.498

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.0293

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.272 AC: 41368 AN: 152158 Hom.: 7080 Cov.: 33 AF XY: 0.265 AC XY: 19730 AN XY: 74400

Gnomad4 AFR AF: 0.487

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.0295

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.246

Alfa AF: 0.238 Hom.: 2059

Bravo AF: 0.289

Asia WGS AF: 0.129 AC: 450 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.79

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: rs704074; hg19: chr12-89742731;