1-6570955-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138697.4(TAS1R1):c.238C>T(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,612,330 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: TAS1R1 NM_138697.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.195

Genes affected

TAS1R1 (HGNC:14448): (taste 1 receptor member 1) The protein encoded by this gene is a G protein-coupled receptor and is a component of the heterodimeric amino acid taste receptor T1R1+3. The T1R1+3 receptor responds to L-amino acids but not to D-enantiomers or other compounds. Most amino acids that are perceived as sweet activate T1R1+3, and this activation is strictly dependent on an intact T1R1+3 heterodimer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

LOC107984912 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAS1R1	NM_138697.4	c.238C>T	p.Arg80Trp	missense_variant	2/6	ENST00000333172.11
LOC107984912	XR_002958250.1	n.88-972G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAS1R1	ENST00000333172.11	c.238C>T	p.Arg80Trp	missense_variant	2/6	1	NM_138697.4	P1
TAS1R1	ENST00000415267.1	c.16C>T	p.Arg6Trp	missense_variant	1/4	1
TAS1R1	ENST00000351136.7	c.238C>T	p.Arg80Trp	missense_variant	2/5	2
TAS1R1	ENST00000411823.5	c.16C>T	p.Arg6Trp	missense_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000562 AC: 14 AN: 248920 Hom.: 0 AF XY: 0.0000669 AC XY: 9 AN XY: 134454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000589 AC: 86 AN: 1460040 Hom.: 0 Cov.: 31 AF XY: 0.0000592 AC XY: 43 AN XY: 726260

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74470

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

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

Apr 13, 2022

The c.238C>T (p.R80W) alteration is located in exon 2 (coding exon 2) of the TAS1R1 gene. This alteration results from a C to T substitution at nucleotide position 238, causing the arginine (R) at amino acid position 80 to be replaced by a tryptophan (W). 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	0.33
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Benign	0.084
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	0.87	D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.66
MVP		0.76
MPC		0.70
ClinPred		0.92	D
GERP RS		1.7
Varity_R		0.96
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199550568; hg19: chr1-6631015; COSMIC: COSV60226673;