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GeneBe

14-59464485-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_022571.6(GPR135):c.742G>C(p.Gly248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000713 in 1,541,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

GPR135
NM_022571.6 missense

Scores

1
1
17

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.89
Variant links:
Genes affected
GPR135 (HGNC:19991): (G protein-coupled receptor 135) Enables arrestin family protein binding activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in endosome and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
L3HYPDH (HGNC:20488): (trans-L-3-hydroxyproline dehydratase) The protein encoded by this gene is a dehydratase that converts trans-3-hydroxy-L-proline to delta(1)-pyrroline-2-carboxylate. This enzyme may function to degrade dietary proteins that contain trans-3-hydroxy-L-proline as well as other proteins such as collagen IV. The encoded protein can be converted to an epimerase by changing a threonine to a cysteine at a catalytic site. [provided by RefSeq, Sep 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.102544576).
BP6
Variant 14-59464485-C-G is Benign according to our data. Variant chr14-59464485-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3101408.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GPR135NM_022571.6 linkuse as main transcriptc.742G>C p.Gly248Arg missense_variant 1/1 ENST00000395116.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GPR135ENST00000395116.2 linkuse as main transcriptc.742G>C p.Gly248Arg missense_variant 1/1 NM_022571.6 P1
GPR135ENST00000481661.1 linkuse as main transcriptc.742G>C p.Gly248Arg missense_variant, NMD_transcript_variant 1/71
L3HYPDHENST00000466522.1 linkuse as main transcriptn.31-3312G>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152120
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000576
AC:
8
AN:
1389724
Hom.:
0
Cov.:
30
AF XY:
0.00000728
AC XY:
5
AN XY:
686408
show subpopulations
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:
0.00
Gnomad4 NFE exome
AF:
0.00000647
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152120
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
Cadd
Benign
2.1
Dann
Benign
0.77
DEOGEN2
Benign
0.0062
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.50
T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.10
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.17
Sift
Benign
0.81
T
Sift4G
Benign
0.56
T
Polyphen
0.0030
B
Vest4
0.11
MutPred
0.74
Gain of helix (P = 0.0325);
MVP
0.52
ClinPred
0.029
T
GERP RS
-5.4
Varity_R
0.055
gMVP
0.49

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs907616963; hg19: chr14-59931203; API