rs704074

Variant names:

• chr12-89348954-T-C
• rs704074
• NM_001946.4:c.*300A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 publications found

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]

DUSP6 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 19 with or without anosmia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

POC1B-DUSP6 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001946.4. 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
	DUSP6	NM_001946.4	MANE Select	c.*300A>G		3_prime_UTR	Exon 3 of 3	NP_001937.2
	POC1B-DUSP6	NM_001425794.1		c.*536A>G		3_prime_UTR	Exon 11 of 11	NP_001412723.1
	POC1B-DUSP6	NM_001425795.1		c.*536A>G		3_prime_UTR	Exon 10 of 10	NP_001412724.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP6	ENST00000279488.8	TSL:1 MANE Select	c.*300A>G		3_prime_UTR	Exon 3 of 3	ENSP00000279488.6	Q16828-1
	DUSP6	ENST00000308385.6	TSL:1	c.*300A>G		3_prime_UTR	Exon 2 of 2	ENSP00000307835.6	Q16828-2
	DUSP6	ENST00000924807.1		c.*300A>G		3_prime_UTR	Exon 3 of 3	ENSP00000594866.1

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

African (AFR) AF: 0.498 AC: 3432 AN: 6896

American (AMR) AF: 0.243 AC: 1854 AN: 7626

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 1065 AN: 5732

East Asian (EAS) AF: 0.0293 AC: 375 AN: 12816

South Asian (SAS) AF: 0.178 AC: 2003 AN: 11240

European-Finnish (FIN) AF: 0.141 AC: 1091 AN: 7738

Middle Eastern (MID) AF: 0.166 AC: 134 AN: 806

European-Non Finnish (NFE) AF: 0.191 AC: 18998 AN: 99210

Other (OTH) AF: 0.203 AC: 2014 AN: 9906

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

African (AFR) AF: 0.487 AC: 20181 AN: 41472

American (AMR) AF: 0.253 AC: 3864 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3468

East Asian (EAS) AF: 0.0295 AC: 153 AN: 5180

South Asian (SAS) AF: 0.167 AC: 806 AN: 4830

European-Finnish (FIN) AF: 0.157 AC: 1661 AN: 10604

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.195 AC: 13268 AN: 68000

Other (OTH) AF: 0.246 AC: 519 AN: 2112

Alfa AF: 0.242 Hom.: 2523

Bravo AF: 0.289

Asia WGS AF: 0.129 AC: 450 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs704074; hg19: chr12-89742731;