Genetic Variant NM_014375.3:c.48C>G (chr3-186640508-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014375.3(FETUB):c.48C>G(p.Cys16Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,614,146 control chromosomes in the GnomAD database, including 454 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 211 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 243 hom. )

Consequence

FETUB
NM_014375.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.70

Publications

1 publications found

Variant links:

Genes affected

FETUB (HGNC:3658): (fetuin B) The protein encoded by this gene is a member of the fetuin family, part of the cystatin superfamily of cysteine protease inhibitors. Fetuins have been implicated in several diverse functions, including osteogenesis and bone resorption, regulation of the insulin and hepatocyte growth factor receptors, and response to systemic inflammation. This protein may be secreted by cells. [provided by RefSeq, Jul 2008]

FETUB links:

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

HRG-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00187096).

BP6

Variant 3-186640508-C-G is Benign according to our data. Variant chr3-186640508-C-G is described in ClinVar as Benign. ClinVar VariationId is 775931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0999 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014375.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FETUB	NM_014375.3	MANE Select	c.48C>G	p.Cys16Trp	missense	Exon 1 of 7	NP_055190.2	Q9UGM5-1
FETUB	NM_001375587.2		c.48C>G	p.Cys16Trp	missense	Exon 2 of 8	NP_001362516.1	Q9UGM5-1
FETUB	NM_001308077.4		c.48C>G	p.Cys16Trp	missense	Exon 1 of 6	NP_001295006.1	Q9UGM5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FETUB	ENST00000265029.8	TSL:1 MANE Select	c.48C>G	p.Cys16Trp	missense	Exon 1 of 7	ENSP00000265029.3	Q9UGM5-1
FETUB	ENST00000450521.5	TSL:1	c.48C>G	p.Cys16Trp	missense	Exon 2 of 8	ENSP00000404288.1	Q9UGM5-1
FETUB	ENST00000382136.3	TSL:1	c.48C>G	p.Cys16Trp	missense	Exon 1 of 6	ENSP00000371571.3	Q9UGM5-2

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4529

AN:

152160

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0125

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.00779

AC:

1955

AN:

251090

AF XY:

0.00557

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00324

AC:

4738

AN:

1461868

Hom.:

243

Cov.:

AF XY:

0.00276

AC XY:

2009

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.110

AC:

3681

AN:

33466

American (AMR)

AF:

0.00566

AC:

253

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000236

AC:

262

AN:

1112008

Other (OTH)

AF:

0.00687

AC:

415

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

257

514

772

1029

1286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.0299

AC:

4548

AN:

152278

Hom.:

211

Cov.:

AF XY:

0.0290

AC XY:

2161

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.102

AC:

4256

AN:

41530

American (AMR)

AF:

0.0125

AC:

191

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68026

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

199

399

598

798

997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.00193

Hom.:

Bravo

AF:

0.0340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0976

AC:

430

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00938

AC:

1139

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.0050

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.11

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.9

PhyloP100

-3.7

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.9

REVEL

Benign

0.22

Sift

Uncertain

0.0050

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.49

MVP

0.13

MPC

0.033

ClinPred

0.11

GERP RS

-10

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.29

gMVP

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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