6-39057543-G-A

Position:

• chr6-39057543-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_002062.5(GLP1R):​c.247G>A​(p.Val83Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GLP1R NM_002062.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.99

Genes affected

GLP1R (HGNC:4324): (glucagon like peptide 1 receptor) This gene encodes a 7-transmembrane protein that functions as a receptor for glucagon-like peptide 1 (GLP-1) hormone, which stimulates glucose-induced insulin secretion. This receptor, which functions at the cell surface, becomes internalized in response to GLP-1 and GLP-1 analogs, and it plays an important role in the signaling cascades leading to insulin secretion. It also displays neuroprotective effects in animal models. Polymorphisms in this gene are associated with diabetes. The protein is an important drug target for the treatment of type 2 diabetes and stroke. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31722414).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLP1R	NM_002062.5	c.247G>A	p.Val83Ile	missense_variant	3/13	ENST00000373256.5	NP_002053.3
GLP1R	NR_136562.2	n.307G>A		non_coding_transcript_exon_variant	3/14
GLP1R	NR_136563.2	n.307G>A		non_coding_transcript_exon_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLP1R	ENST00000373256.5	c.247G>A	p.Val83Ile	missense_variant	3/13	1	NM_002062.5	ENSP00000362353	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460302 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726420

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 08, 2023

The c.247G>A (p.V83I) alteration is located in exon 3 (coding exon 3) of the GLP1R gene. This alteration results from a G to A substitution at nucleotide position 247, causing the valine (V) at amino acid position 83 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	0.10
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.11
Sift	Benign	0.27	T
Sift4G	Benign	0.21	T
Polyphen		0.14	B
Vest4		0.29
MutPred		0.53		Loss of glycosylation at S79 (P = 0.184);
MVP		0.80
MPC		0.70
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.32
gMVP		0.30

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: chr6-39025319;