Genetic Variant GPR135:p.Arg357Gln (chr14-59464157-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022571.6(GPR135):c.1070G>A(p.Arg357Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,456,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

GPR135
NM_022571.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12

Publications

0 publications found

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]

GPR135 links:

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]

L3HYPDH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.092639744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022571.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR135	NM_022571.6	MANE Select	c.1070G>A	p.Arg357Gln	missense	Exon 1 of 1	NP_072093.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPR135	ENST00000395116.2	TSL:6 MANE Select	c.1070G>A	p.Arg357Gln	missense	Exon 1 of 1	ENSP00000378548.1	Q8IZ08
GPR135	ENST00000481661.1	TSL:1	n.1070G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000432696.1	Q8IZ08
L3HYPDH	ENST00000466522.1	TSL:3	n.31-2984G>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000836

AC:

AN:

239200

AF XY:

0.00000762

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000923

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1456400

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

724686

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111646

Other (OTH)

AF:

0.00

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0072

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.63

M_CAP

Benign

0.040

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.64

PhyloP100

3.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.2

REVEL

Benign

0.054

Sift

Benign

0.45

Sift4G

Benign

0.17

Polyphen

0.054

Vest4

0.11

MutPred

0.48

Loss of helix (P = 0.0626)

MVP

0.52

ClinPred

0.15

GERP RS

1.3

Varity_R

0.067

gMVP

0.55

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over