3-71754488-G-T

Position:

• chr3-71754488-G-T

Variant summary

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

The NM_018971.3(GPR27):​c.439G>T​(p.Ala147Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000873 in 1,145,030 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: GPR27 NM_018971.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.47

Genes affected

GPR27 (HGNC:4482): (G protein-coupled receptor 27) GPR27 is a member of the G protein-coupled receptors (GPCRs), a large family of receptors that have a similar structure characterized by 7 transmembrane domains. Activation of GPCRs by extracellular stimuli such as neurotransmitters, hormones, or light induces an intracellular signaling cascade mediated by heterotrimeric GTP-binding proteins, or G proteins.[supplied by OMIM, May 2010]

EIF4E3 (HGNC:31837): (eukaryotic translation initiation factor 4E family member 3) EIF4E3 belongs to the EIF4E family of translational initiation factors that interact with the 5-prime cap structure of mRNA and recruit mRNA to the ribosome (Joshi et al., 2004 [PubMed 15153109]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR27	NM_018971.3	c.439G>T	p.Ala147Ser	missense_variant	1/1	ENST00000304411.3	NP_061844.1
EIF4E3	NM_001134649.3	c.-564C>A		5_prime_UTR_variant	1/8		NP_001128121.1
EIF4E3	XM_047448063.1	c.-686C>A		5_prime_UTR_variant	1/9		XP_047304019.1
EIF4E3	NM_173359.5	c.-291+156C>A		intron_variant			NP_775495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR27	ENST00000304411.3	c.439G>T	p.Ala147Ser	missense_variant	1/1	6	NM_018971.3	ENSP00000303149.2
EIF4E3	ENST00000421769.6	c.-291+156C>A		intron_variant		1		ENSP00000411762.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.73e-7 AC: 1 AN: 1145030 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 555900

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: 0.00000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Sep 27, 2024

The c.439G>T (p.A147S) alteration is located in exon 1 (coding exon 1) of the GPR27 gene. This alteration results from a G to T substitution at nucleotide position 439, causing the alanine (A) at amino acid position 147 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.69		Gain of catalytic residue at L143 (P = 0.2472);
MVP		0.53
ClinPred		0.94	D
GERP RS		0.43
Varity_R		0.25
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

Other links and lift over

dbSNP: rs1303682924; hg19: chr3-71803639;