12-122716221-T-G

Variant names:

• chr12-122716221-T-G
• rs1798192
• NM_006018.3:c.517A>C

Variant summary

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

The ENST00000528880.3(HCAR3):​c.517A>C​(p.Thr173Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,613,782 control chromosomes in the GnomAD database, including 242,548 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.53 (21765 hom., cov: 31)
  • Exomes 𝑓: 0.55 (220783 hom.)
• Consequence: HCAR3 ENST00000528880.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 46 publications found

Genes affected

HCAR3 (HGNC:16824): (hydroxycarboxylic acid receptor 3) Predicted to enable GTP binding activity and purinergic nucleotide receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in cell junction. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000256249 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.5918223E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000528880.3. 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
	HCAR3	NM_006018.3	MANE Select	c.517A>C	p.Thr173Pro	missense	Exon 1 of 1	NP_006009.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCAR3	ENST00000528880.3	TSL:6 MANE Select	c.517A>C	p.Thr173Pro	missense	Exon 1 of 1	ENSP00000436714.2
	ENSG00000256249	ENST00000543611.1	TSL:4	n.*242T>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80494 AN: 151822 Hom.: 21768 Cov.: 31

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.527

GnomAD2 exomes AF: 0.503 AC: 126435 AN: 251384 AF XY: 0.499

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.574

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.505

Gnomad NFE exome AF: 0.572

Gnomad OTH exome AF: 0.536

GnomAD4 exome AF: 0.545 AC: 796877 AN: 1461842 Hom.: 220783 Cov.: 77 AF XY: 0.540 AC XY: 392387 AN XY: 727218

African (AFR) AF: 0.499 AC: 16693 AN: 33478

American (AMR) AF: 0.400 AC: 17901 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 15159 AN: 26134

East Asian (EAS) AF: 0.558 AC: 22135 AN: 39698

South Asian (SAS) AF: 0.331 AC: 28540 AN: 86248

European-Finnish (FIN) AF: 0.504 AC: 26918 AN: 53416

Middle Eastern (MID) AF: 0.516 AC: 2976 AN: 5768

European-Non Finnish (NFE) AF: 0.571 AC: 634697 AN: 1111984

Other (OTH) AF: 0.528 AC: 31858 AN: 60394

GnomAD4 genome AF: 0.530 AC: 80494 AN: 151940 Hom.: 21765 Cov.: 31 AF XY: 0.521 AC XY: 38720 AN XY: 74250

African (AFR) AF: 0.506 AC: 20971 AN: 41424

American (AMR) AF: 0.473 AC: 7214 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1982 AN: 3464

East Asian (EAS) AF: 0.529 AC: 2736 AN: 5170

South Asian (SAS) AF: 0.326 AC: 1566 AN: 4800

European-Finnish (FIN) AF: 0.488 AC: 5147 AN: 10546

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39070 AN: 67964

Other (OTH) AF: 0.520 AC: 1097 AN: 2110

Alfa AF: 0.563 Hom.: 81157

Bravo AF: 0.532

TwinsUK AF: 0.567 AC: 2102

ALSPAC AF: 0.569 AC: 2192

ESP6500AA AF: 0.506 AC: 2231

ESP6500EA AF: 0.572 AC: 4921

ExAC AF: 0.506 AC: 61448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0040
DANN	Benign	0.54
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.000056	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.026
Sift	Benign	0.26	T
Sift4G	Benign	0.39	T
Vest4		0.045
MPC		0.86
ClinPred		0.0079	T
GERP RS		-4.7
Varity_R		0.12
gMVP		0.33
Mutation Taster		=94/6	polymorphism (auto)

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: rs1798192; hg19: chr12-123200768; COSMIC: COSV63672553; COSMIC: COSV63672553;