2-219501527-C-T

Position:

chr2-219501527-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013335.4(GMPPA):c.190C>T(p.Pro64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,613,098 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 11 hom. )

Consequence

GMPPA
NM_013335.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.887

Variant links:

Genes affected

GMPPA (HGNC:22923): (GDP-mannose pyrophosphorylase A) This gene is thought to encode a GDP-mannose pyrophosphorylase. This enzyme catalyzes the reaction which converts mannose-1-phosphate and GTP to GDP-mannose which is involved in the production of N-linked oligosaccharides. [provided by RefSeq, Jul 2008]

GMPPA links:

ASIC4-AS1 (HGNC:40960): (ASIC4 antisense RNA 1)

ASIC4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066054463).

BP6

Variant 2-219501527-C-T is Benign according to our data. Variant chr2-219501527-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 388353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219501527-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0022 (335/152280) while in subpopulation NFE AF= 0.0031 (211/68022). AF 95% confidence interval is 0.00276. There are 0 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMPPA	NM_013335.4 linkuse as main transcript	c.190C>T	p.Pro64Ser	missense_variant	4/13	ENST00000313597.10
ASIC4-AS1	XR_923921.2 linkuse as main transcript	n.391+15169G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMPPA	ENST00000313597.10 linkuse as main transcript	c.190C>T	p.Pro64Ser	missense_variant	4/13	1	NM_013335.4	P1	Q96IJ6-1
ASIC4-AS1	ENST00000429882.1 linkuse as main transcript	n.182+15169G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00220

AC:

335

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00801

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00229

AC:

577

AN:

251478

Hom.:

AF XY:

0.00235

AC XY:

319

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00873

Gnomad NFE exome

AF:

0.00293

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00294

AC:

4301

AN:

1460818

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

2074

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00792

Gnomad4 NFE exome

AF:

0.00331

Gnomad4 OTH exome

AF:

0.00234

GnomAD4 genome

AF:

0.00220

AC:

335

AN:

152280

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00801

Gnomad4 NFE

AF:

0.00310

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00219

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00238

AC:

289

EpiCase

AF:

0.00273

EpiControl

AF:

0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alacrima, achalasia, and intellectual disability syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 16, 2022	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Apr 19, 2017

BS1,BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

GMPPA-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2018

This variant is associated with the following publications: (PMID: 28820871) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.40

T;.;T;T;.;T;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

.;D;.;.;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.0066

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.41

N;N;N;N;.;.;N;.

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.090

N;N;N;N;N;N;N;.

REVEL

Benign

0.16

Sift

Benign

0.42

T;T;T;T;T;T;T;.

Sift4G

Benign

0.72

T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;.;.;B;.

Vest4

0.27

MVP

0.72

MPC

0.39

ClinPred

0.0085

GERP RS

-2.4

Varity_R

0.040

gMVP

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over