12-122715747-G-A

Position:

• chr12-122715747-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006018.3(HCAR3):​c.991C>T​(p.Leu331Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCAR3 NM_006018.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17965358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCAR3	NM_006018.3	c.991C>T	p.Leu331Phe	missense_variant	1/1	ENST00000528880.3	NP_006009.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCAR3	ENST00000528880.3	c.991C>T	p.Leu331Phe	missense_variant	1/1	6	NM_006018.3	ENSP00000436714.2
ENSG00000256249	ENST00000543611.1	n.1499G>A		non_coding_transcript_exon_variant	3/3	4
ENSG00000256249	ENST00000545293.1	n.*39G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000343 AC: 5 AN: 1459096 Hom.: 0 Cov.: 39 AF XY: 0.00000413 AC XY: 3 AN XY: 725920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000824 AC: 1

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

Oct 26, 2022

The c.991C>T (p.L331F) alteration is located in exon 1 (coding exon 1) of the HCAR3 gene. This alteration results from a C to T substitution at nucleotide position 991, causing the leucine (L) at amino acid position 331 to be replaced by a phenylalanine (F). 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	0.097
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.15
Sift	Benign	0.054	T
Sift4G	Benign	0.061	T
Vest4		0.077
MutPred		0.21		Loss of stability (P = 0.0722);
MVP		0.53
MPC		1.6
ClinPred		0.78	D
GERP RS		3.4
Varity_R		0.11
gMVP		0.14

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: rs768930200; hg19: chr12-123200294;