rs2250145

Variant names:

• chr5-147906491-G-A
• rs2250145
• NM_206966.3:c.11C>T

Variant summary

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

The NM_206966.3(C5orf46):​c.11C>T​(p.Ser4Leu) variant causes a missense change. The variant allele was found at a frequency of 0.567 in 1,605,674 control chromosomes in the GnomAD database, including 264,490 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.48 (19592 hom., cov: 32)
  • Exomes 𝑓: 0.58 (244898 hom.)
• Consequence: C5orf46 NM_206966.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• Publications: 38 publications found

Genes affected

C5orf46 (HGNC:33768): (chromosome 5 open reading frame 46) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.6146898E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206966.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5orf46	NM_206966.3	MANE Select	c.11C>T	p.Ser4Leu	missense	Exon 1 of 4	NP_996849.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5orf46	ENST00000318315.5	TSL:1 MANE Select	c.11C>T	p.Ser4Leu	missense	Exon 1 of 4	ENSP00000315370.4
	C5orf46	ENST00000515291.1	TSL:1	c.11C>T	p.Ser4Leu	missense	Exon 1 of 2	ENSP00000425984.1
	C5orf46	ENST00000955897.1		c.11C>T	p.Ser4Leu	missense	Exon 1 of 4	ENSP00000625956.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 72973 AN: 151832 Hom.: 19599 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.502

GnomAD2 exomes AF: 0.557 AC: 138793 AN: 249138 AF XY: 0.569

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.617

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.592

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.576 AC: 837181 AN: 1453724 Hom.: 244898 Cov.: 31 AF XY: 0.579 AC XY: 418608 AN XY: 723140

African (AFR) AF: 0.219 AC: 7309 AN: 33374

American (AMR) AF: 0.458 AC: 20371 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 14354 AN: 26048

East Asian (EAS) AF: 0.597 AC: 23638 AN: 39594

South Asian (SAS) AF: 0.611 AC: 51998 AN: 85144

European-Finnish (FIN) AF: 0.651 AC: 34692 AN: 53328

Middle Eastern (MID) AF: 0.496 AC: 2853 AN: 5748

European-Non Finnish (NFE) AF: 0.586 AC: 648528 AN: 1105820

Other (OTH) AF: 0.556 AC: 33438 AN: 60168

GnomAD4 genome AF: 0.480 AC: 72970 AN: 151950 Hom.: 19592 Cov.: 32 AF XY: 0.484 AC XY: 35972 AN XY: 74252

African (AFR) AF: 0.227 AC: 9401 AN: 41462

American (AMR) AF: 0.473 AC: 7212 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1860 AN: 3470

East Asian (EAS) AF: 0.602 AC: 3096 AN: 5140

South Asian (SAS) AF: 0.599 AC: 2882 AN: 4808

European-Finnish (FIN) AF: 0.660 AC: 6970 AN: 10558

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.587 AC: 39876 AN: 67944

Other (OTH) AF: 0.497 AC: 1049 AN: 2110

Alfa AF: 0.553 Hom.: 115275

Bravo AF: 0.459

TwinsUK AF: 0.583 AC: 2161

ALSPAC AF: 0.573 AC: 2207

ESP6500AA AF: 0.227 AC: 1001

ESP6500EA AF: 0.585 AC: 5030

ExAC AF: 0.557 AC: 67606

Asia WGS AF: 0.510 AC: 1773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.00016	T
MetaSVM	Benign	-0.83	T
PhyloP100		4.2
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.21
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.45
MPC		0.18
ClinPred		0.027	T
GERP RS		4.9
PromoterAI		-0.028	Neutral
Varity_R		0.32
gMVP		0.31
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2250145; hg19: chr5-147286054; COSMIC: COSV59153993; COSMIC: COSV59153993;