chr14-59464215-C-T

Position:

• chr14-59464215-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022571.6(GPR135):​c.1012G>A​(p.Val338Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,458,896 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GPR135 NM_022571.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07962838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR135	NM_022571.6	c.1012G>A	p.Val338Ile	missense_variant	1/1	ENST00000395116.2	NP_072093.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR135	ENST00000395116.2	c.1012G>A	p.Val338Ile	missense_variant	1/1		NM_022571.6	ENSP00000378548	P1
GPR135	ENST00000481661.1	c.1012G>A	p.Val338Ile	missense_variant, NMD_transcript_variant	1/7	1		ENSP00000432696
L3HYPDH	ENST00000466522.1	n.31-3042G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1458896 Hom.: 0 Cov.: 30 AF XY: 0.0000207 AC XY: 15 AN XY: 725890

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2023

The c.1012G>A (p.V338I) alteration is located in exon 1 (coding exon 1) of the GPR135 gene. This alteration results from a G to A substitution at nucleotide position 1012, causing the valine (V) at amino acid position 338 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.8
DANN	Benign	0.95
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.056
Sift	Benign	0.46	T
Sift4G	Benign	0.50	T
Polyphen		0.21	B
Vest4		0.13
MutPred		0.55		Loss of catalytic residue at V338 (P = 0.0057);
MVP		0.18
ClinPred		0.19	T
GERP RS		-2.4
Varity_R		0.029
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-59930933;