rs2291533

Variant names:

• chr3-63831754-G-C
• rs2291533
• NM_001355236.2:c.759G>C

Variant summary

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

The NM_001355236.2(C3orf49):​c.759G>C​(p.Gln253His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 702,790 control chromosomes in the GnomAD database, including 10,620 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.15 (1872 hom., cov: 32)
  • Exomes 𝑓: 0.17 (8748 hom.)
• Consequence: C3orf49 NM_001355236.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• Publications: 12 publications found

Genes affected

C3orf49 (HGNC:25190): (chromosome 3 open reading frame 49)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013246536).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3orf49	NM_001355236.2	c.759G>C	p.Gln253His	missense_variant	Exon 5 of 7	ENST00000295896.13	NP_001342165.1
C3orf49	XM_024453353.2	c.759G>C	p.Gln253His	missense_variant	Exon 6 of 6		XP_024309121.1
C3orf49	XM_047447470.1	c.555G>C	p.Gln185His	missense_variant	Exon 5 of 5		XP_047303426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3orf49	ENST00000295896.13	c.759G>C	p.Gln253His	missense_variant	Exon 5 of 7	2	NM_001355236.2	ENSP00000295896.8
C3orf49	ENST00000647022.1	c.759G>C	p.Gln253His	missense_variant	Exon 5 of 5			ENSP00000495997.1
C3orf49	ENST00000491896.1	c.384G>C	p.Gln128His	missense_variant	Exon 4 of 4	2		ENSP00000494182.1
C3orf49	ENST00000673037.1	c.624G>C	p.Gln208His	missense_variant, splice_region_variant	Exon 4 of 5			ENSP00000500910.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22869 AN: 152050 Hom.: 1873 Cov.: 32

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.175 AC: 24528 AN: 139890 AF XY: 0.175

Gnomad AFR exome AF: 0.0760

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.174 AC: 95788 AN: 550622 Hom.: 8748 Cov.: 0 AF XY: 0.172 AC XY: 51380 AN XY: 298102

African (AFR) AF: 0.0784 AC: 1239 AN: 15800

American (AMR) AF: 0.212 AC: 7342 AN: 34676

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 3919 AN: 20030

East Asian (EAS) AF: 0.131 AC: 4219 AN: 32096

South Asian (SAS) AF: 0.144 AC: 9016 AN: 62736

European-Finnish (FIN) AF: 0.142 AC: 4762 AN: 33636

Middle Eastern (MID) AF: 0.149 AC: 608 AN: 4076

European-Non Finnish (NFE) AF: 0.188 AC: 59512 AN: 316940

Other (OTH) AF: 0.169 AC: 5171 AN: 30632

GnomAD4 genome AF: 0.150 AC: 22872 AN: 152168 Hom.: 1872 Cov.: 32 AF XY: 0.148 AC XY: 11034 AN XY: 74404

African (AFR) AF: 0.0784 AC: 3256 AN: 41536

American (AMR) AF: 0.179 AC: 2736 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3470

East Asian (EAS) AF: 0.139 AC: 718 AN: 5160

South Asian (SAS) AF: 0.138 AC: 665 AN: 4810

European-Finnish (FIN) AF: 0.136 AC: 1438 AN: 10590

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12842 AN: 68000

Other (OTH) AF: 0.172 AC: 364 AN: 2114

Alfa AF: 0.167 Hom.: 399

Bravo AF: 0.153

TwinsUK AF: 0.182 AC: 675

ALSPAC AF: 0.190 AC: 732

ExAC AF: 0.137 AC: 2558

Asia WGS AF: 0.122 AC: 427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.099	.;T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.54	T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		0.31
PROVEAN	Uncertain	-3.5	.;D;.;.
REVEL	Benign	0.081
Sift	Uncertain	0.017	.;D;.;.
Sift4G	Benign	0.27	.;T;T;.
Polyphen		0.0010	.;B;.;.
Vest4		0.075
MutPred		0.16		Loss of disorder (P = 0.0793);Loss of disorder (P = 0.0793);Loss of disorder (P = 0.0793);.;
ClinPred		0.035	T
GERP RS		1.1
Varity_R		0.26
gMVP		0.034
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2291533; hg19: chr3-63817430; COSMIC: COSV55732830; COSMIC: COSV55732830;