Genetic Variant BTLA:p.Arg157Ser (chr3-112471290-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_181780.4(BTLA):c.469C>A(p.Arg157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,114 control chromosomes in the GnomAD database, including 804,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.99 ( 74813 hom., cov: 31)

Exomes 𝑓: 1.0 ( 729352 hom. )

Consequence

BTLA
NM_181780.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.49

Publications

28 publications found

Variant links:

Genes affected

BTLA (HGNC:21087): (B and T lymphocyte associated) This gene encodes a member of the immunoglobulin superfamily. The encoded protein contains a single immunoglobulin (Ig) domain and is a receptor that relays inhibitory signals to suppress the immune response. Alternative splicing results in multiple transcript variants. Polymorphisms in this gene have been associated with an increased risk of rheumatoid arthritis. [provided by RefSeq, Aug 2011]

BTLA links:

ENSG00000303317 (HGNC:):

ENSG00000303317 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.1498323E-7).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTLA	NM_181780.4 link	c.469C>A	p.Arg157Ser	missense_variant	Exon 3 of 5	ENST00000334529.10	NP_861445.4	Q7Z6A9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BTLA	ENST00000334529.10 link	c.469C>A	p.Arg157Ser	missense_variant	Exon 3 of 5	1	NM_181780.4	ENSP00000333919.5	Q7Z6A9-1
BTLA	ENST00000383680.5 link	c.404-1486C>A		intron_variant	Intron 2 of 3	1		ENSP00000373178.4	Q7Z6A9-2
ENSG00000303317	ENST00000793585.1 link	n.393-46718G>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.991

AC:

150825

AN:

152164

Hom.:

74759

Cov.:

show subpopulations

Gnomad AFR

AF:

0.970

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.997

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

0.995

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.992

GnomAD2 exomes

AF:

0.997

AC:

250749

AN:

251438

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.968

Gnomad AMR exome

AF:

0.999

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

0.994

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.999

GnomAD4 exome

AF:

0.999

AC:

1460239

AN:

1461832

Hom.:

729352

Cov.:

AF XY:

0.999

AC XY:

726514

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.967

AC:

32372

AN:

33472

American (AMR)

AF:

0.999

AC:

44661

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26134

AN:

26134

East Asian (EAS)

AF:

0.995

AC:

39496

AN:

39696

South Asian (SAS)

AF:

0.999

AC:

86201

AN:

86254

European-Finnish (FIN)

AF:

1.00

AC:

53420

AN:

53420

Middle Eastern (MID)

AF:

0.997

AC:

5751

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111958

AN:

1111970

Other (OTH)

AF:

0.998

AC:

60246

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<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:

0.991

AC:

150938

AN:

152282

Hom.:

74813

Cov.:

AF XY:

0.992

AC XY:

73851

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.970

AC:

40292

AN:

41542

American (AMR)

AF:

0.997

AC:

15262

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

0.995

AC:

5154

AN:

5180

South Asian (SAS)

AF:

0.999

AC:

4814

AN:

4820

European-Finnish (FIN)

AF:

1.00

AC:

10612

AN:

10612

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68029

AN:

68032

Other (OTH)

AF:

0.992

AC:

2098

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.997

Hom.:

183227

Bravo

AF:

0.990

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.972

AC:

4284

ESP6500EA

AF:

1.00

AC:

8600

ExAC

AF:

0.997

AC:

121035

Asia WGS

AF:

0.991

AC:

3446

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.14

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.093

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.068

MetaRNN

Benign

7.1e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

-1.5

PrimateAI

Benign

0.22

PROVEAN

Benign

1.3

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.045

MPC

0.69

ClinPred

0.010

GERP RS

-4.9

Varity_R

0.10

gMVP

0.34

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over