11-126304167-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_014026.6(DCPS):c.87G>T(p.Glu29Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000508 in 1,614,276 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: DCPS NM_014026.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.593

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]

TIRAP-AS1 (HGNC:56069): (TIRAP antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046408176).
• BP6: Variant 11-126304167-G-T is Benign according to our data. Variant chr11-126304167-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500319.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000493 (720/1461888) while in subpopulation MID AF= 0.0127 (73/5768). AF 95% confidence interval is 0.0103. There are 3 homozygotes in gnomad4_exome. There are 359 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCPS	NM_014026.6	c.87G>T	p.Glu29Asp	missense_variant	1/6	ENST00000263579.5
DCPS	NM_001350236.2	c.87G>T	p.Glu29Asp	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCPS	ENST00000263579.5	c.87G>T	p.Glu29Asp	missense_variant	1/6	1	NM_014026.6	P1
TIRAP-AS1	ENST00000524964.2	n.116+41C>A		intron_variant, non_coding_transcript_variant		2
TIRAP-AS1	ENST00000693424.1	n.133C>A		non_coding_transcript_exon_variant	1/1
TIRAP-AS1	ENST00000691542.1	n.114+41C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152270 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000712 AC: 179 AN: 251372 Hom.: 0 AF XY: 0.000706 AC XY: 96 AN XY: 135896

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000493 AC: 720 AN: 1461888 Hom.: 3 Cov.: 31 AF XY: 0.000494 AC XY: 359 AN XY: 727242

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152388 Hom.: 1 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74518

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000772 Hom.: 0

Bravo AF: 0.000616

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.00104

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2017	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

The c.87G>T (p.E29D) alteration is located in exon 1 (coding exon 1) of the DCPS gene. This alteration results from a G to T substitution at nucleotide position 87, causing the glutamic acid (E) at amino acid position 29 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	4.3
Dann	Benign	0.96
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.024
Sift	Benign	0.29	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.46		Gain of loop (P = 0.0195);
MVP		0.22
MPC		0.10
ClinPred		0.013	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.065
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs147935593; hg19: chr11-126174062;