rs140377449

Positions:

• chr11-126345390-G-A
• chr11-126345390-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS2

The NM_014026.6(DCPS):​c.791G>A​(p.Arg264Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,614,164 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (4 hom.)
• Consequence: DCPS NM_014026.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.60

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]

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

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.10115048).
• BP6: Variant 11-126345390-G-A is Benign according to our data. Variant chr11-126345390-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCPS	NM_014026.6	c.791G>A	p.Arg264Gln	missense_variant	6/6	ENST00000263579.5
GSEC	NR_033839.1	n.147-3068C>T		intron_variant, non_coding_transcript_variant
DCPS	NM_001350236.2	c.812G>A	p.Arg271Gln	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCPS	ENST00000263579.5	c.791G>A	p.Arg264Gln	missense_variant	6/6	1	NM_014026.6	P1
GSEC	ENST00000629441.3	n.147-3068C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000931 AC: 234 AN: 251224 Hom.: 1 AF XY: 0.00117 AC XY: 159 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00418

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000746 AC: 1091 AN: 1461812 Hom.: 4 Cov.: 31 AF XY: 0.000884 AC XY: 643 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00396

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000587

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000738 AC XY: 55 AN XY: 74508

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000627 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000955 AC: 116

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 31, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.96
MVP		0.96
MPC		0.58
ClinPred		0.34	T
GERP RS		5.2
Varity_R		0.91
gMVP		0.91

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: rs140377449; hg19: chr11-126215285;