12-122716221-T-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006018.3(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. 14/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.53 (21765 hom., cov: 31)
  • Exomes 𝑓: 0.55 (220783 hom.)
• Consequence: HCAR3 NM_006018.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCAR3	NM_006018.3	c.517A>C	p.Thr173Pro	missense_variant	Exon 1 of 1	ENST00000528880.3	NP_006009.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCAR3	ENST00000528880.3	c.517A>C	p.Thr173Pro	missense_variant	Exon 1 of 1	6	NM_006018.3	ENSP00000436714.2
ENSG00000256249	ENST00000543611.1	n.*242T>G		downstream_gene_variant		4

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

GnomAD3 exomes AF: 0.503 AC: 126435 AN: 251384 Hom.: 33087 AF XY: 0.499 AC XY: 67792 AN XY: 135854

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 SAS exome AF: 0.321

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

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.580

Gnomad4 EAS exome AF: 0.558

Gnomad4 SAS exome AF: 0.331

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.571

Gnomad4 OTH exome AF: 0.528

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

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.529

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.520

Alfa AF: 0.560 Hom.: 40707

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 v4.3

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
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

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