12-8059495-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004054.4(C3AR1):c.691C>A(p.Pro231Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C3AR1 NM_004054.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.750

Genes affected

C3AR1 (HGNC:1319): (complement C3a receptor 1) C3a is an anaphylatoxin released during activation of the complement system. The protein encoded by this gene is an orphan G protein-coupled receptor for C3a. Binding of C3a by the encoded receptor activates chemotaxis, granule enzyme release, superoxide anion production, and bacterial opsonization. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043522745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C3AR1	NM_004054.4	c.691C>A	p.Pro231Thr	missense_variant	2/2	ENST00000307637.5
C3AR1	NM_001326475.2	c.691C>A	p.Pro231Thr	missense_variant	2/2
C3AR1	NM_001326477.2	c.691C>A	p.Pro231Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3AR1	ENST00000307637.5	c.691C>A	p.Pro231Thr	missense_variant	2/2	1	NM_004054.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 08, 2022

The c.691C>A (p.P231T) alteration is located in exon 2 (coding exon 1) of the C3AR1 gene. This alteration results from a C to A substitution at nucleotide position 691, causing the proline (P) at amino acid position 231 to be replaced by a threonine (T). 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	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.11
Dann	Benign	0.36
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.048
Sift	Benign	0.52	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.036
MutPred		0.46		Gain of sheet (P = 0.0477);
MVP		0.24
MPC		0.032
ClinPred		0.083	T
GERP RS		-6.3
Varity_R		0.025
gMVP		0.45

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: rs1947243548; hg19: chr12-8212091;