dbSNP rs137941190: DCPS:p.Thr316Met (chr11-126345546-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PS3PP5BP4BS1_SupportingBS2

The NM_014026.6(DCPS):c.947C>T(p.Thr316Met) variant causes a missense change. The variant allele was found at a frequency of 0.000551 in 1,613,974 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001142428: "In vitro decapping assays showed an ablation of decapping function for both variants in DCPS." PMID:25701870".

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 7 hom. )

Consequence

DCPS
NM_014026.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 3.75

Publications

11 publications found

Variant links:

Genes affected

DCPS (HGNC:29812): (decapping enzyme, scavenger) This gene encodes a member of the histidine triad family of pyrophosphatases that removes short mRNA fragments containing the 5′ mRNA cap structure, which appear in the 3′ → 5′ mRNA decay pathway, following deadenylation and exosome-mediated turnover. This enzyme hydrolyzes the triphosphate linkage of the cap structure (7-methylguanosine nucleoside triphosphate) to yield 7-methylguanosine monophosphate and nucleoside diphosphate. It protects the cell from the potentially toxic accumulation of these short, capped mRNA fragments, and regulates the activity of other cap-binding proteins, which are inhibited by their accumulation. It also acts as a transcript-specific modulator of pre-mRNA splicing and microRNA turnover. [provided by RefSeq, Apr 2017]

DCPS links:

GSEC (HGNC:48645): (G-quadruplex forming sequence containing lncRNA)

GSEC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001142428: "In vitro decapping assays showed an ablation of decapping function for both variants in DCPS." PMID:25701870

PP5

Variant 11-126345546-C-T is Pathogenic according to our data. Variant chr11-126345546-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372235.

BP4

Computational evidence support a benign effect (MetaRNN=0.020261317). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000302 (46/152328) while in subpopulation SAS AF = 0.00787 (38/4830). AF 95% confidence interval is 0.00589. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014026.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DCPS	NM_014026.6	MANE Select	c.947C>T	p.Thr316Met	missense	Exon 6 of 6	NP_054745.1	A0A384MTI8
DCPS	NM_001350236.2		c.968C>T	p.Thr323Met	missense	Exon 6 of 6	NP_001337165.1
GSEC	NR_033839.1		n.147-3224G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DCPS	ENST00000263579.5	TSL:1 MANE Select	c.947C>T	p.Thr316Met	missense	Exon 6 of 6	ENSP00000263579.4	Q96C86
DCPS	ENST00000861222.1		c.968C>T	p.Thr323Met	missense	Exon 6 of 6	ENSP00000531281.1
DCPS	ENST00000912051.1		c.944C>T	p.Thr315Met	missense	Exon 6 of 6	ENSP00000582110.1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00120

AC:

302

AN:

251084

AF XY:

0.00158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000577

AC:

843

AN:

1461646

Hom.:

Cov.:

AF XY:

0.000816

AC XY:

593

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00876

AC:

756

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53180

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1112008

Other (OTH)

AF:

0.000414

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41580

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00787

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000427

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00130

AC:

158

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Al-Raqad syndrome (7)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.0

PhyloP100

3.7

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.43

MVP

0.72

MPC

0.41

ClinPred

0.20

GERP RS

4.5

Varity_R

0.53

gMVP

0.88

Mutation Taster

=73/27

disease causing (ClinVar)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over