12-11091518-A-G

Variant names:

• chr12-11091518-A-G
• rs3759245
• NM_176884.2:c.712T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_176884.2(TAS2R43):​c.712T>C​(p.Cys238Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,280,436 control chromosomes in the GnomAD database, including 17,846 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.095 (1034 hom., cov: 24)
  • Exomes 𝑓: 0.072 (16812 hom.)
• Consequence: TAS2R43 NM_176884.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 12 publications found

Genes affected

TAS2R43 (HGNC:18875): (taste 2 receptor member 43) TAS2R43 belongs to the large TAS2R receptor family. TAS2Rs are expressed on the surface of taste receptor cells and mediate the perception of bitterness through a G protein-coupled second messenger pathway (Conte et al., 2002 [PubMed 12584440]). For further information on TAS2Rs, see MIM 604791.[supplied by OMIM, Mar 2009]

ENSG00000275778 (HGNC:):

PRH1 (HGNC:9366): (proline rich protein HaeIII subfamily 1) This gene encodes a member of the heterogeneous family of proline-rich salivary glycoproteins. The encoded preproprotein undergoes proteolytic processing to generate one or more mature isoforms before secretion from the parotid and submandibular/sublingual glands. Multiple distinct alleles of this locus including the parotid isoelectric-focusing variant slow (PIF-s), the parotid acidic protein (Pa), and the double band slow (Db-s) isoforms have been characterized. The reference genome encodes the Db-s allele. Certain alleles of this gene are associated with susceptibility to dental caries. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. Co-transcription of this gene with adjacent genes has been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

PRR4 (HGNC:18020): (proline rich 4) This gene encodes a member of the proline-rich protein family that lacks a conserved repetitive domain. This protein may play a role in protective functions in the eye. Alternative splicing result in multiple transcript variants. Read-through transcription also exists between this gene and the upstream PRH1 (proline-rich protein HaeIII subfamily 1) gene. [provided by RefSeq, Feb 2011]

TAS2R14 (HGNC:14920): (taste 2 receptor member 14) This gene product belongs to the family of candidate taste receptors that are members of the G-protein-coupled receptor superfamily. These proteins are specifically expressed in the taste receptor cells of the tongue and palate epithelia. They are organized in the genome in clusters and are genetically linked to loci that influence bitter perception in mice and humans. In functional expression studies, they respond to bitter tastants. This gene maps to the taste receptor gene cluster on chromosome 12p13. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032700896).
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176884.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R43	NM_176884.2	MANE Select	c.712T>C	p.Cys238Arg	missense	Exon 1 of 1	NP_795365.2
	PRH1	NM_001291315.2		c.-133-44330T>C		intron	N/A	NP_001278244.1
	PRH1	NM_001291314.2		c.-294-44330T>C		intron	N/A	NP_001278243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R43	ENST00000531678.1	TSL:6 MANE Select	c.712T>C	p.Cys238Arg	missense	Exon 1 of 1	ENSP00000431719.1
	ENSG00000275778	ENST00000536668.2	TSL:5	n.-164-44330T>C		intron	N/A	ENSP00000482961.1
	PRR4	ENST00000535024.7	TSL:5	c.-133-44330T>C		intron	N/A	ENSP00000481571.3

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 10832 AN: 114512 Hom.: 1033 Cov.: 24

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0807

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.0748

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0659

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0798

GnomAD2 exomes AF: 0.0212 AC: 4553 AN: 214462 AF XY: 0.0212

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.00480

Gnomad EAS exome AF: 0.00770

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0321

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0716 AC: 83521 AN: 1165822 Hom.: 16812 Cov.: 53 AF XY: 0.0730 AC XY: 42526 AN XY: 582680

African (AFR) AF: 0.0472 AC: 1329 AN: 28134

American (AMR) AF: 0.0835 AC: 2951 AN: 35326

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 814 AN: 22238

East Asian (EAS) AF: 0.0503 AC: 1493 AN: 29700

South Asian (SAS) AF: 0.0353 AC: 2514 AN: 71134

European-Finnish (FIN) AF: 0.148 AC: 6319 AN: 42642

Middle Eastern (MID) AF: 0.0413 AC: 200 AN: 4842

European-Non Finnish (NFE) AF: 0.0730 AC: 64444 AN: 882962

Other (OTH) AF: 0.0708 AC: 3457 AN: 48844

GnomAD4 genome AF: 0.0945 AC: 10836 AN: 114614 Hom.: 1034 Cov.: 24 AF XY: 0.0955 AC XY: 5325 AN XY: 55762

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0778 AC: 2506 AN: 32194

American (AMR) AF: 0.0810 AC: 919 AN: 11348

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 187 AN: 2868

East Asian (EAS) AF: 0.0748 AC: 303 AN: 4052

South Asian (SAS) AF: 0.0533 AC: 205 AN: 3844

European-Finnish (FIN) AF: 0.118 AC: 835 AN: 7090

Middle Eastern (MID) AF: 0.0672 AC: 16 AN: 238

European-Non Finnish (NFE) AF: 0.112 AC: 5693 AN: 50670

Other (OTH) AF: 0.0801 AC: 126 AN: 1574

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0993 Hom.: 481

ExAC AF: 0.0706 AC: 8520

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.58
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.077	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.078
Sift	Benign	0.075	T
Sift4G	Benign	0.098	T
Polyphen		0.0010	B
Vest4		0.13
MPC		0.19
ClinPred		0.0063	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs3759245; hg19: chr12-11244117; COSMIC: COSV67851513;