Genetic Variant BTG4:p.Arg194His (chr11-111495244-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001367975.1(BTG4):c.581G>A(p.Arg194His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,612,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

BTG4
NM_001367975.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.570

Publications

2 publications found

Variant links:

Genes affected

BTG4 (HGNC:13862): (BTG anti-proliferation factor 4) The protein encoded by this gene is a member of the BTG/Tob family. This family has structurally related proteins that appear to have antiproliferative properties. This encoded protein can induce G1 arrest in the cell cycle. [provided by RefSeq, Jul 2008]

BTG4 Gene-Disease associations (from GenCC):

oocyte maturation defect 8
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
female infertility
Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox

BTG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03900078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTG4	NM_001367975.1 link	c.581G>A	p.Arg194His	missense_variant	Exon 5 of 5	ENST00000692032.1	NP_001354904.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BTG4	ENST00000692032.1 link	c.581G>A	p.Arg194His	missense_variant	Exon 5 of 5		NM_001367975.1	ENSP00000509850.1	A0A8I5KVE8
BTG4	ENST00000689553.1 link	c.581G>A	p.Arg194His	missense_variant	Exon 7 of 7			ENSP00000508793.1	A0A8I5KVE8
BTG4	ENST00000356018.6 link	c.581G>A	p.Arg194His	missense_variant	Exon 5 of 6	5		ENSP00000348300.2	Q9NY30-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000762

AC:

AN:

249324

AF XY:

0.0000890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000594

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000712

AC:

104

AN:

1460216

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

726398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.0000903

AC:

AN:

44320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39638

South Asian (SAS)

AF:

0.0000349

AC:

AN:

85864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000783

AC:

AN:

1111394

Other (OTH)

AF:

0.0000994

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41506

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000234

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.581G>A (p.R194H) alteration is located in exon 5 (coding exon 4) of the BTG4 gene. This alteration results from a G to A substitution at nucleotide position 581, causing the arginine (R) at amino acid position 194 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.48

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.072

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.69

M_CAP

Benign

0.0053

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.57

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.36

REVEL

Benign

0.055

Sift

Benign

0.16

Sift4G

Benign

0.49

Polyphen

0.0080

Vest4

0.078

MVP

0.16

MPC

0.22

ClinPred

0.033

GERP RS

0.64

Varity_R

0.025

gMVP

0.26

Mutation Taster

=97/3

polymorphism

(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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11-111495244-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over