6-167156886-C-T

Variant names:

• chr6-167156886-C-T
• rs780218828
• NM_005299.3:c.946G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005299.3(GPR31):​c.946G>A​(p.Asp316Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,600,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GPR31 NM_005299.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.830
• Publications: 0 publications found

Genes affected

GPR31 (HGNC:4486): (G protein-coupled receptor 31) Enables G protein-coupled receptor activity and arachidonic acid binding activity. Involved in G protein-coupled receptor signaling pathway and response to acidic pH. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000291286 (HGNC:):

ACMG classification

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=0.0846709).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR31	NM_005299.3	c.946G>A	p.Asp316Asn	missense_variant	Exon 1 of 1	ENST00000366834.2	NP_005290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR31	ENST00000366834.2	c.946G>A	p.Asp316Asn	missense_variant	Exon 1 of 1	6	NM_005299.3	ENSP00000355799.2
ENSG00000291286	ENST00000486697.2	n.122+6813C>T		intron_variant	Intron 2 of 3	5
ENSG00000291286	ENST00000539001.6	n.368+7402C>T		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241732 AF XY: 0.00

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: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1448642 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 10 AN XY: 719494

African (AFR) AF: 0.00 AC: 0 AN: 32916

American (AMR) AF: 0.00 AC: 0 AN: 43002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 84272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1105428

Other (OTH) AF: 0.0000167 AC: 1 AN: 59714

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000315 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.946G>A (p.D316N) alteration is located in exon 1 (coding exon 1) of the GPR31 gene. This alteration results from a G to A substitution at nucleotide position 946, causing the aspartic acid (D) at amino acid position 316 to be replaced by an asparagine (N). 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	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.83
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.042
Sift	Benign	0.18	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.33	B
Vest4		0.23
MutPred		0.17		Gain of catalytic residue at D316 (P = 0.0221);
MVP		0.50
MPC		0.15
ClinPred		0.14	T
GERP RS		2.6
Varity_R		0.10
gMVP		0.096
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs780218828; hg19: chr6-167570374;