rs1555409827

Variant names:

• chr14-91234215-CAGTTGAAGCTGGTGAGCAGGAGGGAGAAGTGGTAGGCGTTGAAAACGCCCTTGGCGAAGTCGCAGCTGGCCTCCCAGACGCTGCGCACCAGCAGCAACACGTGGTAGGGCAGGAAGCAGGCCAGGAAGATGACCACGGTGCTGAGCACCAGCCGCTGGATCTGGTCCTTGCGGCTCTTCTGGGTGCCGTGGCTCCGGCGCACGGCGCGCAGGATGCCCTGGTAGGACGCCAGCAGCAGGCAGATGGGGAAGAGGAAGCCCACCAGGAAGCGGTAGTAGTTGATGGCGCGCTGCCATGCCTGGATGGGGTAGTGCTCAAAGCACACGCGGTGCTGGTTCTCGTCCTCGATGACCTCCTCGTGCATCAGGAAGTAGATGCTGGTCAGCAGCTCCTTGGCCCAGATGACCACGCTGACGCCGACGGCCGCCTTCAGGGTCCGGAACTGGTGGA-C
• rs1555409827
• NM_001177676.2:c.386_835del

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP3 PP5

The NM_001177676.2(GPR68):​c.386_835del​(p.Phe129_Asn278del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR68 NM_001177676.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

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]

GPR68 Gene-Disease associations (from GenCC):

• amelogenesis imperfecta, hypomaturation type, IIa6

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001177676.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 14-91234215-CAGTTGAAGCTGGTGAGCAGGAGGGAGAAGTGGTAGGCGTTGAAAACGCCCTTGGCGAAGTCGCAGCTGGCCTCCCAGACGCTGCGCACCAGCAGCAACACGTGGTAGGGCAGGAAGCAGGCCAGGAAGATGACCACGGTGCTGAGCACCAGCCGCTGGATCTGGTCCTTGCGGCTCTTCTGGGTGCCGTGGCTCCGGCGCACGGCGCGCAGGATGCCCTGGTAGGACGCCAGCAGCAGGCAGATGGGGAAGAGGAAGCCCACCAGGAAGCGGTAGTAGTTGATGGCGCGCTGCCATGCCTGGATGGGGTAGTGCTCAAAGCACACGCGGTGCTGGTTCTCGTCCTCGATGACCTCCTCGTGCATCAGGAAGTAGATGCTGGTCAGCAGCTCCTTGGCCCAGATGACCACGCTGACGCCGACGGCCGCCTTCAGGGTCCGGAACTGGTGGA-C is Pathogenic according to our data. Variant chr14-91234215-CAGTTGAAGCTGGTGAGCAGGAGGGAGAAGTGGTAGGCGTTGAAAACGCCCTTGGCGAAGTCGCAGCTGGCCTCCCAGACGCTGCGCACCAGCAGCAACACGTGGTAGGGCAGGAAGCAGGCCAGGAAGATGACCACGGTGCTGAGCACCAGCCGCTGGATCTGGTCCTTGCGGCTCTTCTGGGTGCCGTGGCTCCGGCGCACGGCGCGCAGGATGCCCTGGTAGGACGCCAGCAGCAGGCAGATGGGGAAGAGGAAGCCCACCAGGAAGCGGTAGTAGTTGATGGCGCGCTGCCATGCCTGGATGGGGTAGTGCTCAAAGCACACGCGGTGCTGGTTCTCGTCCTCGATGACCTCCTCGTGCATCAGGAAGTAGATGCTGGTCAGCAGCTCCTTGGCCCAGATGACCACGCTGACGCCGACGGCCGCCTTCAGGGTCCGGAACTGGTGGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 268084.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177676.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR68	NM_001177676.2	MANE Select	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	NP_001171147.1
	GPR68	NM_001348437.1		c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 3 of 3	NP_001335366.1
	GPR68	NM_003485.3		c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	NP_003476.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR68	ENST00000650645.1	MANE Select	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000498702.1
	GPR68	ENST00000531499.2	TSL:1	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000434045.2
	GPR68	ENST00000535815.5	TSL:1	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000440797.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Amelogenesis imperfecta (1)
1	-	-	Amelogenesis imperfecta, hypomaturation type, IIa6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555409827; hg19: chr14-91700559;