12-11092003-T-C

Variant names:

• chr12-11092003-T-C
• rs11535673
• NM_176884.2:c.227A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_176884.2(TAS2R43):​c.227A>G​(p.Asn76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.060 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0081 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TAS2R43 NM_176884.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.406
• Publications: 9 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004627675).
• BP6: Variant 12-11092003-T-C is Benign according to our data. Variant chr12-11092003-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 771455.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R43	NM_176884.2	MANE Select	c.227A>G	p.Asn76Ser	missense	Exon 1 of 1	NP_795365.2	P59537
	PRH1	NM_001291315.2		c.-133-44815A>G		intron	N/A	NP_001278244.1
	PRH1	NM_001291314.2		c.-294-44815A>G		intron	N/A	NP_001278243.1	A0A087WV42

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R43	ENST00000531678.1	TSL:6 MANE Select	c.227A>G	p.Asn76Ser	missense	Exon 1 of 1	ENSP00000431719.1	P59537
	ENSG00000275778	ENST00000536668.2	TSL:5	n.-164-44815A>G		intron	N/A	ENSP00000482961.1	A0A087WZY1
	PRR4	ENST00000535024.7	TSL:5	c.-133-44815A>G		intron	N/A	ENSP00000481571.3	A0A087WY73

Frequencies

GnomAD3 genomes AF: 0.0605 AC: 4958 AN: 81988 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00972

Gnomad AMI AF: 0.0646

Gnomad AMR AF: 0.0929

Gnomad ASJ AF: 0.0897

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0685

GnomAD2 exomes AF: 0.0000200 AC: 4 AN: 199958 AF XY: 0.0000183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000580

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000237

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00809 AC: 7261 AN: 897260 Hom.: 0 Cov.: 56 AF XY: 0.00837 AC XY: 3764 AN XY: 449510

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

African (AFR) AF: 0.000775 AC: 23 AN: 29684

American (AMR) AF: 0.0274 AC: 691 AN: 25224

Ashkenazi Jewish (ASJ) AF: 0.00615 AC: 96 AN: 15610

East Asian (EAS) AF: 0.0238 AC: 382 AN: 16064

South Asian (SAS) AF: 0.0162 AC: 816 AN: 50322

European-Finnish (FIN) AF: 0.00805 AC: 248 AN: 30804

Middle Eastern (MID) AF: 0.00546 AC: 19 AN: 3482

European-Non Finnish (NFE) AF: 0.00683 AC: 4708 AN: 689008

Other (OTH) AF: 0.00750 AC: 278 AN: 37062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0604 AC: 4955 AN: 82080 Hom.: 0 Cov.: 20 AF XY: 0.0656 AC XY: 2584 AN XY: 39382

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

African (AFR) AF: 0.00969 AC: 311 AN: 32100

American (AMR) AF: 0.0929 AC: 668 AN: 7192

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 149 AN: 1662

East Asian (EAS) AF: 0.189 AC: 372 AN: 1968

South Asian (SAS) AF: 0.121 AC: 278 AN: 2298

European-Finnish (FIN) AF: 0.149 AC: 563 AN: 3776

Middle Eastern (MID) AF: 0.0929 AC: 13 AN: 140

European-Non Finnish (NFE) AF: 0.0795 AC: 2496 AN: 31406

Other (OTH) AF: 0.0696 AC: 78 AN: 1120

⚠️ 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: 0.0574 Hom.: 0

ExAC AF: 0.00628 AC: 745

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.67
DANN	Benign	0.45
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N
PhyloP100		-0.41
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.0090
Sift	Benign	0.33	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.23
MPC		0.083
ClinPred		0.098	T
GERP RS		0.73
PromoterAI		-0.0062	Neutral
Varity_R		0.055
gMVP		0.046
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs11535673; hg19: chr12-11244602; COSMIC: COSV67860443;