rs4467185

Positions:

• chr19-47319781-G-A
• chr19-47319781-G-C
• chr19-47319781-G-T

Variant summary

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

The NM_001736.4(C5AR1):​c.4G>A​(p.Asp2Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.983 in 1,594,666 control chromosomes in the GnomAD database, including 771,229 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.97 (71770 hom., cov: 31)
  • Exomes 𝑓: 0.98 (699459 hom.)
• Consequence: C5AR1 NM_001736.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002932
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.254

Genes affected

C5AR1 (HGNC:1338): (complement C5a receptor 1) Enables G protein-coupled receptor activity and complement component C5a receptor activity. Involved in several processes, including complement component C5a signaling pathway; mRNA transcription by RNA polymerase II; and positive regulation of ERK1 and ERK2 cascade. Located in apical part of cell and basolateral plasma membrane. Biomarker of Alzheimer's disease; asthma; chronic obstructive pulmonary disease; rhinitis; and severe acute respiratory syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0422458E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5AR1	NM_001736.4	c.4G>A	p.Asp2Asn	missense_variant, splice_region_variant	2/2	ENST00000355085.4
C5AR1	XM_047439300.1	c.106G>A	p.Asp36Asn	missense_variant, splice_region_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5AR1	ENST00000355085.4	c.4G>A	p.Asp2Asn	missense_variant, splice_region_variant	2/2	1	NM_001736.4	P1
C5AR1	ENST00000594787.1	c.-354G>A		splice_region_variant, 5_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.971 AC: 147685 AN: 152120 Hom.: 71738 Cov.: 31

Gnomad AFR AF: 0.933

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.976

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.983

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.958

GnomAD3 exomes AF: 0.982 AC: 244208 AN: 248698 Hom.: 119957 AF XY: 0.982 AC XY: 131949 AN XY: 134352

Gnomad AFR exome AF: 0.933

Gnomad AMR exome AF: 0.980

Gnomad ASJ exome AF: 0.978

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.984

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.984

Gnomad OTH exome AF: 0.975

GnomAD4 exome AF: 0.985 AC: 1420342 AN: 1442428 Hom.: 699459 Cov.: 28 AF XY: 0.985 AC XY: 707188 AN XY: 718306

Gnomad4 AFR exome AF: 0.933

Gnomad4 AMR exome AF: 0.980

Gnomad4 ASJ exome AF: 0.977

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.983

Gnomad4 FIN exome AF: 0.996

Gnomad4 NFE exome AF: 0.986

Gnomad4 OTH exome AF: 0.979

GnomAD4 genome AF: 0.971 AC: 147771 AN: 152238 Hom.: 71770 Cov.: 31 AF XY: 0.971 AC XY: 72258 AN XY: 74418

Gnomad4 AFR AF: 0.933

Gnomad4 AMR AF: 0.976

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.983

Gnomad4 FIN AF: 0.996

Gnomad4 NFE AF: 0.985

Gnomad4 OTH AF: 0.959

Alfa AF: 0.979 Hom.: 150648

Bravo AF: 0.967

TwinsUK AF: 0.985 AC: 3654

ALSPAC AF: 0.986 AC: 3801

ESP6500AA AF: 0.936 AC: 4126

ESP6500EA AF: 0.983 AC: 8456

ExAC AF: 0.982 AC: 119172

Asia WGS AF: 0.981 AC: 3412 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.023
Sift	Benign	0.38	T
Sift4G	Benign	0.066	T
Polyphen		0.0050	B
Vest4		0.018
MPC		0.34
ClinPred		0.0048	T
GERP RS		1.7
Varity_R		0.070
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.0020
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: rs4467185; hg19: chr19-47823038;