rs35836343

Variant names:

• chr11-126343347-G-A
• rs35836343
• NM_014026.6:c.677G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014026.6(DCPS):​c.677G>A​(p.Gly226Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,613,898 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (31 hom.)
• Consequence: DCPS NM_014026.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.49
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012222111).
• BP6: Variant 11-126343347-G-A is Benign according to our data. Variant chr11-126343347-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.004 (609/152242) while in subpopulation NFE AF = 0.00588 (400/68014). AF 95% confidence interval is 0.00541. There are 9 homozygotes in GnomAd4. There are 265 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCPS	NM_014026.6	MANE Select	c.677G>A	p.Gly226Asp	missense	Exon 5 of 6	NP_054745.1	A0A384MTI8
	DCPS	NM_001350236.2		c.698G>A	p.Gly233Asp	missense	Exon 5 of 6	NP_001337165.1
	GSEC	NR_033839.1		n.147-1025C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCPS	ENST00000263579.5	TSL:1 MANE Select	c.677G>A	p.Gly226Asp	missense	Exon 5 of 6	ENSP00000263579.4	Q96C86
	DCPS	ENST00000861222.1		c.698G>A	p.Gly233Asp	missense	Exon 5 of 6	ENSP00000531281.1
	DCPS	ENST00000912051.1		c.677G>A	p.Gly226Asp	missense	Exon 5 of 6	ENSP00000582110.1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152124 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00447 AC: 1121 AN: 250816 AF XY: 0.00441

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00500 AC: 7313 AN: 1461656 Hom.: 31 Cov.: 32 AF XY: 0.00505 AC XY: 3673 AN XY: 727110

African (AFR) AF: 0.000896 AC: 30 AN: 33474

American (AMR) AF: 0.00161 AC: 72 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 821 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86208

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53350

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00540 AC: 6006 AN: 1111916

Other (OTH) AF: 0.00507 AC: 306 AN: 60390

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152242 Hom.: 9 Cov.: 31 AF XY: 0.00356 AC XY: 265 AN XY: 74418

African (AFR) AF: 0.000866 AC: 36 AN: 41560

American (AMR) AF: 0.00190 AC: 29 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00588 AC: 400 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00601 Hom.: 13

Bravo AF: 0.00429

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00768 AC: 66

ExAC AF: 0.00396 AC: 481

EpiCase AF: 0.00589

EpiControl AF: 0.00611

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Al-Raqad syndrome (1)
-	-	1	DCPS-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.17	N
PhyloP100		1.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.38
Sift	Benign	0.27	T
Sift4G	Benign	0.60	T
Polyphen		0.018	B
Vest4		0.33
MVP		0.68
MPC		0.15
ClinPred		0.023	T
GERP RS		0.20
Varity_R		0.43
gMVP		0.77
Mutation Taster		=75/25	polymorphism

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: rs35836343; hg19: chr11-126213242; COSMIC: COSV99703650;