rs61746390

Positions:

• chrX-41696517-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The ENST00000378142.9(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 ENST00000378142.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20

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]

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]

ACMG classification

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	c.884A>G	p.Asn295Ser	missense_variant	3/3	ENST00000378142.9	NP_001091048.1
CASK	NM_001367721.1	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	c.884A>G	p.Asn295Ser	missense_variant	3/3	1	NM_001097579.2	ENSP00000367384	P1
CASK	ENST00000378163.7	c.430-24987T>C		intron_variant		5	NM_001367721.1	ENSP00000367405	A1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 1935 AN: 112017 Hom.: 35 Cov.: 23 AF XY: 0.0155 AC XY: 528 AN XY: 34169

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.: 19 AF XY: 0.00378 AC XY: 254 AN XY: 67243

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.: 53 Cov.: 30 AF XY: 0.00169 AC XY: 611 AN XY: 361245

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.: 35 Cov.: 23 AF XY: 0.0154 AC XY: 528 AN XY: 34233

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.: 91

Bravo AF: 0.0214

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.0602 AC: 231

ESP6500EA AF: 0.00 AC: 0

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

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	T
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	N
LIST_S2	Benign	0.74	.;.;T;T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L;L;.;L
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs61746390; hg19: chrX-41555770;