Genetic Variant NM_181780.4:c.590A>C (chr3-112469762-T-G) – 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.590A>C(p.Asn197Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00851 in 1,600,692 control chromosomes in the GnomAD database, including 520 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.023 ( 90 hom., cov: 31)

Exomes 𝑓: 0.0071 ( 430 hom. )

Consequence

BTLA
NM_181780.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.296

Publications

18 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:

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=0.0020754635).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTLA	NM_181780.4 link	c.590A>C	p.Asn197Thr	missense_variant	Exon 4 of 5	ENST00000334529.10	NP_861445.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTLA	ENST00000334529.10 link	c.590A>C	p.Asn197Thr	missense_variant	Exon 4 of 5	1	NM_181780.4	ENSP00000333919.5

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3239

AN:

142018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0490

Gnomad AMI

AF:

0.00234

Gnomad AMR

AF:

0.0582

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0746

Gnomad SAS

AF:

0.00971

Gnomad FIN

AF:

0.000104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.0178

GnomAD2 exomes

AF:

0.0236

AC:

5906

AN:

249746

AF XY:

0.0190

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0687

Gnomad FIN exome

AF:

0.000244

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.00711

AC:

10374

AN:

1458552

Hom.:

430

Cov.:

AF XY:

0.00655

AC XY:

4754

AN XY:

725742

show subpopulations

African (AFR)

AF:

0.0514

AC:

1715

AN:

33388

American (AMR)

AF:

0.0952

AC:

4245

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0770

AC:

3048

AN:

39560

South Asian (SAS)

AF:

0.00682

AC:

588

AN:

86194

European-Finnish (FIN)

AF:

0.000270

AC:

AN:

51804

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000199

AC:

221

AN:

1110842

Other (OTH)

AF:

0.00864

AC:

521

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

481

961

1442

1922

2403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.0229

AC:

3255

AN:

142140

Hom.:

Cov.:

AF XY:

0.0235

AC XY:

1630

AN XY:

69274

show subpopulations

African (AFR)

AF:

0.0491

AC:

1946

AN:

39660

American (AMR)

AF:

0.0585

AC:

820

AN:

14014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3230

East Asian (EAS)

AF:

0.0750

AC:

368

AN:

4908

South Asian (SAS)

AF:

0.00972

AC:

AN:

4320

European-Finnish (FIN)

AF:

0.000104

AC:

AN:

9594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

63342

Other (OTH)

AF:

0.0181

AC:

AN:

1936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

133

267

400

534

667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00707

Hom.:

Bravo

AF:

0.0288

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0454

AC:

200

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0211

AC:

2557

Asia WGS

AF:

0.0370

AC:

130

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.26

DEOGEN2

Uncertain

0.50

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.36

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PhyloP100

0.30

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.081

Sift

Benign

0.22

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0030

B;B

Vest4

0.055

MPC

0.64

ClinPred

0.0076

GERP RS

-0.53

Varity_R

0.080

gMVP

0.29

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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