rs76844316

Positions:

• chr3-112469762-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/20 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
BTLA	NM_181780.4	c.590A>C	p.Asn197Thr	missense_variant	4/5	ENST00000334529.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTLA	ENST00000334529.10	c.590A>C	p.Asn197Thr	missense_variant	4/5	1	NM_181780.4	P2
BTLA	ENST00000383680.4	c.446A>C	p.Asn149Thr	missense_variant	3/4	1		A2
BTLA	ENST00000474965.1	n.94A>C		non_coding_transcript_exon_variant	2/3	2
BTLA	ENST00000496584.1	n.525A>C		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3239 AN: 142018 Hom.: 90 Cov.: 31

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

GnomAD3 exomes AF: 0.0236 AC: 5906 AN: 249746 Hom.: 287 AF XY: 0.0190 AC XY: 2573 AN XY: 135136

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 SAS exome AF: 0.00651

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.: 30 AF XY: 0.00655 AC XY: 4754 AN XY: 725742

Gnomad4 AFR exome AF: 0.0514

Gnomad4 AMR exome AF: 0.0952

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0770

Gnomad4 SAS exome AF: 0.00682

Gnomad4 FIN exome AF: 0.000270

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.00864

GnomAD4 genome AF: 0.0229 AC: 3255 AN: 142140 Hom.: 90 Cov.: 31 AF XY: 0.0235 AC XY: 1630 AN XY: 69274

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0750

Gnomad4 SAS AF: 0.00972

Gnomad4 FIN AF: 0.000104

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.0181

Alfa AF: 0.00350 Hom.: 25

Bravo AF: 0.0288

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.00105 AC: 9

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	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.26
DEOGEN2	Uncertain	0.50	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
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	T
GERP RS		-0.53
Varity_R		0.080
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs76844316; hg19: chr3-112188609; COSMIC: COSV57938633;