dbSNP rs774132315: GPR135:p.Ala440Ser (chr14-59463909-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022571.6(GPR135):c.1318G>T(p.Ala440Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A440T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GPR135
NM_022571.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.29

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 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=0.03626138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR135	NM_022571.6 link	c.1318G>T	p.Ala440Ser	missense_variant	Exon 1 of 1	ENST00000395116.2	NP_072093.2	Q8IZ08

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPR135	ENST00000395116.2 link	c.1318G>T	p.Ala440Ser	missense_variant	Exon 1 of 1	6	NM_022571.6	ENSP00000378548.1	Q8IZ08
GPR135	ENST00000481661.1 link	n.1318G>T		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000432696.1	Q8IZ08
L3HYPDH	ENST00000466522.1 link	n.31-2736G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727098

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.7

DANN

Benign

0.97

DEOGEN2

Benign

0.0011

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.45

M_CAP

Benign

0.028

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.11

REVEL

Benign

0.040

Sift

Benign

0.25

Sift4G

Benign

0.16

Polyphen

0.22

Vest4

0.069

MutPred

0.18

Gain of phosphorylation at A440 (P = 0.0148);

MVP

0.21

ClinPred

0.13

GERP RS

2.0

Varity_R

0.040

gMVP

0.33

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over