rs16859633

chr3-112479488-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_181780.4(BTLA):c.370A>G(p.Ile124Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,613,586 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0044 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (8 hom.)
• Consequence: BTLA NM_181780.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158

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=0.003258437).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000477 (697/1461238) while in subpopulation AFR AF= 0.0185 (620/33452). AF 95% confidence interval is 0.0173. There are 8 homozygotes in gnomad4_exome. There are 288 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTLA	NM_181780.4	c.370A>G	p.Ile124Val	missense_variant	2/5	ENST00000334529.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTLA	ENST00000334529.10	c.370A>G	p.Ile124Val	missense_variant	2/5	1	NM_181780.4	P2
BTLA	ENST00000383680.4	c.370A>G	p.Ile124Val	missense_variant	2/4	1		A2

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 673 AN: 152230 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00121 AC: 303 AN: 250924 Hom.: 2 AF XY: 0.000796 AC XY: 108 AN XY: 135656

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000477 AC: 697 AN: 1461238 Hom.: 8 Cov.: 31 AF XY: 0.000396 AC XY: 288 AN XY: 726874

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.00442 AC: 673 AN: 152348 Hom.: 7 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74502

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000921 Hom.: 2

Bravo AF: 0.00502

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.054
Dann	Benign	0.45
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.010
Sift	Benign	0.17	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.091	B;B
Vest4		0.036
MVP		0.45
MPC		0.52
ClinPred		0.0016	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.32

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: rs16859633; hg19: chr3-112198335; COSMIC: COSV99080072;