6-39073726-A-T

Position:

• chr6-39073726-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002062.5(GLP1R):​c.780A>T​(p.Leu260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GLP1R NM_002062.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.656

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06533489).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLP1R	NM_002062.5	c.780A>T	p.Leu260Phe	missense_variant	7/13	ENST00000373256.5
GLP1R	NR_136562.2	n.840A>T		non_coding_transcript_exon_variant	7/14
GLP1R	NR_136563.2	n.840A>T		non_coding_transcript_exon_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLP1R	ENST00000373256.5	c.780A>T	p.Leu260Phe	missense_variant	7/13	1	NM_002062.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461722 Hom.: 0 Cov.: 43 AF XY: 0.00000825 AC XY: 6 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000360

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.074
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	3.4	N
REVEL	Benign	0.054
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MutPred		0.56		Gain of glycosylation at S258 (P = 0.1894);
MVP		0.38
MPC		0.51
ClinPred		0.031	T
GERP RS		3.9
Varity_R		0.063
gMVP		0.37

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: rs1042044; hg19: chr6-39041502;