rs1057517672

Positions:

• chr14-91234830-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001177676.2(GPR68):​c.221T>C​(p.Leu74Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GPR68 NM_001177676.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.32

Genes affected

GPR68 (HGNC:4519): (G protein-coupled receptor 68) The protein encoded by this gene is a G protein-coupled receptor for sphingosylphosphorylcholine. The encoded protein is a proton-sensing receptor, inactive at pH 7.8 but active at pH 6.8. Mutations in this gene are a cause of amelogenesis imperfecta. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 14-91234830-A-G is Pathogenic according to our data. Variant chr14-91234830-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 268086.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR68	NM_001177676.2	c.221T>C	p.Leu74Pro	missense_variant	2/2	ENST00000650645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR68	ENST00000650645.1	c.221T>C	p.Leu74Pro	missense_variant	2/2		NM_001177676.2	P1
GPR68	ENST00000531499.2	c.221T>C	p.Leu74Pro	missense_variant	2/2	1		P1
GPR68	ENST00000535815.5	c.221T>C	p.Leu74Pro	missense_variant	2/2	1		P1
GPR68	ENST00000529102.1	c.221T>C	p.Leu74Pro	missense_variant	2/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460894 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Amelogenesis imperfecta, hypomaturation type, IIa6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 21, 2016

- -

Amelogenesis imperfecta Pathogenic:1

Pathogenic, no assertion criteria provided

research

Leeds Amelogenesis Imperfecta Research Group, University of Leeds

Aug 01, 2016

Predicted to alter a residue in the second transmembrane domain -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.8	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.73		Gain of catalytic residue at L74 (P = 0);Gain of catalytic residue at L74 (P = 0);Gain of catalytic residue at L74 (P = 0);
MVP		0.68
MPC		2.4
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98

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: rs1057517672; hg19: chr14-91701174;