Genetic Variant NM_206966.3:c.11C>T (chr5-147906491-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.24

Publications

38 publications found

Variant links:

Genes affected

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

C5orf46 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.579

AC XY:

418608

AN XY:

723140

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

14824

29648

44472

59296

74120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17654

35308

52962

70616

88270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.480

AC:

72970

AN:

151950

Hom.:

19592

Cov.:

AF XY:

0.484

AC XY:

35972

AN XY:

74252

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1774

3547

5321

7094

8868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.78

MetaRNN

Benign

0.00016

MetaSVM

Benign

-0.83

PhyloP100

4.2

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.21

Sift

Benign

0.12

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.45

MPC

0.18

ClinPred

0.027

GERP RS

4.9

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.32

gMVP

0.31

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over