Genetic Variant BTC:p.Leu44Phe (chr4-74770091-G-A) – 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_001729.4(BTC):c.130C>T(p.Leu44Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,613,172 control chromosomes in the GnomAD database, including 406 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.029 ( 220 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 186 hom. )

Consequence

BTC
NM_001729.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.51

Variant links:

Genes affected

BTC (HGNC:1121): (betacellulin) This gene encodes a member of the epidermal growth factor (EGF) family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the secreted growth factor. A secreted form and a membrane-anchored form of this protein bind to multiple different EGF receptors. This protein promotes pancreatic cell proliferation and insulin secretion, as well as retinal vascular permeability. Mutations in this gene may be associated with type 2 diabetes in human patients. [provided by RefSeq, Nov 2015]

BTC links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.001920402).

BP6

Variant 4-74770091-G-A is Benign according to our data. Variant chr4-74770091-G-A is described in ClinVar as [Benign]. Clinvar id is 780468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTC	NM_001729.4 link	c.130C>T	p.Leu44Phe	missense_variant	Exon 2 of 6	ENST00000395743.8	NP_001720.1	P35070A0A0S2Z437

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTC	ENST00000395743.8 link	c.130C>T	p.Leu44Phe	missense_variant	Exon 2 of 6	1	NM_001729.4	ENSP00000379092.3		P35070
BTC	ENST00000512743.1 link	c.64C>T	p.Leu22Phe	missense_variant	Exon 1 of 4	5		ENSP00000421747.1		H0Y8Q5

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

4356

AN:

152098

Hom.:

220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0997

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.00718

AC:

1800

AN:

250870

AF XY:

0.00521

show subpopulations

Gnomad AFR exome

AF:

0.0999

Gnomad AMR exome

AF:

0.00375

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00287

AC:

4190

AN:

1460956

Hom.:

186

Cov.:

AF XY:

0.00242

AC XY:

1762

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.103

AC:

3428

AN:

33378

American (AMR)

AF:

0.00428

AC:

191

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39662

South Asian (SAS)

AF:

0.000116

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00521

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000142

AC:

158

AN:

1111504

Other (OTH)

AF:

0.00616

AC:

372

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

171

342

514

685

856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0287

AC:

4364

AN:

152216

Hom.:

220

Cov.:

AF XY:

0.0276

AC XY:

2056

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0996

AC:

4136

AN:

41514

American (AMR)

AF:

0.00975

AC:

149

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68024

Other (OTH)

AF:

0.0255

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

189

379

568

758

947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00898

Hom.:

128

Bravo

AF:

0.0331

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.102

AC:

450

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00919

AC:

1116

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

-0.035

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

1.5

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

REVEL

Benign

0.037

Sift

Benign

0.082

Sift4G

Benign

0.11

Polyphen

0.99

Vest4

0.085

MVP

0.50

MPC

0.032

ClinPred

0.016

GERP RS

2.3

PromoterAI

0.0036

Neutral

(source)

Varity_R

0.032

gMVP

0.56

Mutation Taster

=97/3

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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chr4-74770091-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over