rs2250145

chr5-147906491-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5orf46	NM_206966.3	c.11C>T	p.Ser4Leu	missense_variant	1/4	ENST00000318315.5
C5orf46	XM_005268446.4	c.11C>T	p.Ser4Leu	missense_variant	1/4
C5orf46	XM_047417169.1	c.11C>T	p.Ser4Leu	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5orf46	ENST00000318315.5	c.11C>T	p.Ser4Leu	missense_variant	1/4	1	NM_206966.3	P1
C5orf46	ENST00000515291.1	c.11C>T	p.Ser4Leu	missense_variant	1/2	1
C5orf46	ENST00000510432.1			upstream_gene_variant		4

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

GnomAD3 exomes AF: 0.557 AC: 138793 AN: 249138 Hom.: 40240 AF XY: 0.569 AC XY: 76583 AN XY: 134574

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 SAS exome AF: 0.612

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

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.458

Gnomad4 ASJ exome AF: 0.551

Gnomad4 EAS exome AF: 0.597

Gnomad4 SAS exome AF: 0.611

Gnomad4 FIN exome AF: 0.651

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.556

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

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.536

Gnomad4 EAS AF: 0.602

Gnomad4 SAS AF: 0.599

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.587

Gnomad4 OTH AF: 0.497

Alfa AF: 0.566 Hom.: 63439

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 v4.3

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;T
MetaRNN	Benign	0.00016	T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.38	P;P
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Benign	0.21
Sift	Benign	0.12	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.45
MPC		0.18
ClinPred		0.027	T
GERP RS		4.9
Varity_R		0.32
gMVP		0.31

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