X-41695561-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001097579.2(GPR34):​c.-73T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR34	NM_001097579.2	c.-73T>A		5_prime_UTR_variant	Exon 3 of 3	ENST00000378142.9	NP_001091048.1
CASK	NM_001367721.1	c.430-24031A>T		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>A		5_prime_UTR_variant	Exon 3 of 3	1	NM_001097579.2	ENSP00000367384.4
CASK	ENST00000378163.7	c.430-24031A>T		intron_variant	Intron 5 of 26	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 580839 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 164785

African (AFR) AF: 0.00 AC: 0 AN: 15181

American (AMR) AF: 0.00 AC: 0 AN: 21784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12002

East Asian (EAS) AF: 0.00 AC: 0 AN: 27409

South Asian (SAS) AF: 0.00 AC: 0 AN: 32864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37249

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3008

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 403304

Other (OTH) AF: 0.00 AC: 0 AN: 28038

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.7
DANN	Benign	0.75
PhyloP100		0.88

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;