X-41695561-T-C

Variant names:

• chrX-41695561-T-C
• rs913602
• NM_001097579.2:c.-73T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001097579.2(GPR34):​c.-73T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.80 (25454 hom., 25825 hem., cov: 22)
  • Exomes 𝑓: 0.79 (129675 hom. 131544 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPR34 NM_001097579.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.882
• Publications: 8 publications found

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]

CASK Gene-Disease associations (from GenCC):

• FG syndrome 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR34	NM_001097579.2	c.-73T>C		5_prime_UTR_variant	Exon 3 of 3	ENST00000378142.9	NP_001091048.1
CASK	NM_001367721.1	c.430-24031A>G		intron_variant	Intron 5 of 26	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR34	ENST00000378142.9	c.-73T>C		5_prime_UTR_variant	Exon 3 of 3	1	NM_001097579.2	ENSP00000367384.4
CASK	ENST00000378163.7	c.430-24031A>G		intron_variant	Intron 5 of 26	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 88490 AN: 110011 Hom.: 25454 Cov.: 22

Gnomad AFR AF: 0.863

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.992

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.713

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.785

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.790 AC: 458612 AN: 580191 Hom.: 129675 Cov.: 9 AF XY: 0.799 AC XY: 131544 AN XY: 164693

African (AFR) AF: 0.871 AC: 13212 AN: 15175

American (AMR) AF: 0.897 AC: 19536 AN: 21771

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 8191 AN: 11984

East Asian (EAS) AF: 0.985 AC: 27004 AN: 27407

South Asian (SAS) AF: 0.861 AC: 28299 AN: 32857

European-Finnish (FIN) AF: 0.679 AC: 25300 AN: 37239

Middle Eastern (MID) AF: 0.720 AC: 2164 AN: 3006

European-Non Finnish (NFE) AF: 0.777 AC: 312739 AN: 402734

Other (OTH) AF: 0.791 AC: 22167 AN: 28018

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.804 AC: 88524 AN: 110058 Hom.: 25454 Cov.: 22 AF XY: 0.800 AC XY: 25825 AN XY: 32280

African (AFR) AF: 0.863 AC: 26087 AN: 30244

American (AMR) AF: 0.846 AC: 8711 AN: 10296

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 1810 AN: 2634

East Asian (EAS) AF: 0.992 AC: 3508 AN: 3537

South Asian (SAS) AF: 0.859 AC: 2200 AN: 2560

European-Finnish (FIN) AF: 0.661 AC: 3738 AN: 5654

Middle Eastern (MID) AF: 0.688 AC: 148 AN: 215

European-Non Finnish (NFE) AF: 0.769 AC: 40577 AN: 52759

Other (OTH) AF: 0.788 AC: 1175 AN: 1491

Alfa AF: 0.786 Hom.: 58962

Bravo AF: 0.822

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		0.88
Mutation Taster		=299/1	polymorphism (auto)

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: rs913602; hg19: chrX-41554814;