rs61746390

Positions:

chrX-41696517-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001097579.2(GPR34):c.884A>G(p.Asn295Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,207,802 control chromosomes in the GnomAD database, including 88 homozygotes. There are 1,139 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 35 hom., 528 hem., cov: 23)

Exomes 𝑓: 0.0020 ( 53 hom. 611 hem. )

Consequence

GPR34
NM_001097579.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.20

Variant links:

Genes affected

GPR34 (HGNC:4490): (G protein-coupled receptor 34) G protein-coupled receptors (GPCRs), such as GPR34, are integral membrane proteins containing 7 putative transmembrane domains (TMs). These proteins mediate signals to the interior of the cell via activation of heterotrimeric G proteins that in turn activate various effector proteins, ultimately resulting in a physiologic response.[supplied by OMIM, Apr 2006]

GPR34 links:

CASK (HGNC:1497): (calcium/calmodulin dependent serine protein kinase) This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

CASK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity GPR34_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0028212368).

BP6

Variant X-41696517-A-G is Benign according to our data. Variant chrX-41696517-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 235298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR34	NM_001097579.2 link	c.884A>G	p.Asn295Ser	missense_variant	3/3	ENST00000378142.9	NP_001091048.1	Q9UPC5Q5VT14
CASK	NM_001367721.1 link	c.430-24987T>C		intron_variant		ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR34	ENST00000378142.9 link	c.884A>G	p.Asn295Ser	missense_variant	3/3	1	NM_001097579.2	ENSP00000367384.4		Q9UPC5
CASK	ENST00000378163.7 link	c.430-24987T>C		intron_variant		5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

1935

AN:

112017

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

528

AN XY:

34169

show subpopulations

Gnomad AFR

AF:

0.0579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.000225

Gnomad OTH

AF:

0.0146

GnomAD3 exomes

AF:

0.00530

AC:

968

AN:

182555

Hom.:

AF XY:

0.00378

AC XY:

254

AN XY:

67243

show subpopulations

Gnomad AFR exome

AF:

0.0630

Gnomad AMR exome

AF:

0.00409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.00333

GnomAD4 exome

AF:

0.00202

AC:

2218

AN:

1095731

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

611

AN XY:

361245

show subpopulations

Gnomad4 AFR exome

AF:

0.0649

Gnomad4 AMR exome

AF:

0.00480

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000203

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.00478

GnomAD4 genome

AF:

0.0173

AC:

1938

AN:

112071

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

528

AN XY:

34233

show subpopulations

Gnomad4 AFR

AF:

0.0578

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000369

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000225

Gnomad4 OTH

AF:

0.0144

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.0214

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.0602

AC:

231

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00591

AC:

718

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.91

CADD

Benign

8.5

DANN

Benign

0.68

DEOGEN2

Benign

0.055

T;T;.;T

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.74

.;.;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.93

L;L;.;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.28

N;N;.;.

REVEL

Benign

0.033

Sift

Benign

0.28

T;T;.;.

Sift4G

Benign

0.59

T;T;T;.

Polyphen

0.014

B;B;.;B

Vest4

0.034

MVP

0.53

MPC

0.56

ClinPred

0.0071

GERP RS

3.3

Varity_R

0.064

gMVP

0.098

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