rs16859633

Variant names:

• chr3-112479488-T-C
• rs16859633
• NM_181780.4:c.370A>G

Variant summary

Our verdict is Benign. The variant received -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. 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 0.0044 (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
• Publications: 11 publications found

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]

ENSG00000303317 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003258437).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 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 GnomAdExome4. There are 288 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181780.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTLA	NM_181780.4	MANE Select	c.370A>G	p.Ile124Val	missense	Exon 2 of 5	NP_861445.4	Q7Z6A9-1
	BTLA	NM_001085357.2		c.370A>G	p.Ile124Val	missense	Exon 2 of 4	NP_001078826.1	Q7Z6A9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTLA	ENST00000334529.10	TSL:1 MANE Select	c.370A>G	p.Ile124Val	missense	Exon 2 of 5	ENSP00000333919.5	Q7Z6A9-1
	BTLA	ENST00000383680.5	TSL:1	c.370A>G	p.Ile124Val	missense	Exon 2 of 4	ENSP00000373178.4	Q7Z6A9-2
	BTLA	ENST00000858278.1		c.370A>G	p.Ile124Val	missense	Exon 3 of 6	ENSP00000528337.1

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

GnomAD2 exomes AF: 0.00121 AC: 303 AN: 250924 AF XY: 0.000796

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 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

African (AFR) AF: 0.0185 AC: 620 AN: 33452

American (AMR) AF: 0.000559 AC: 25 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111550

Other (OTH) AF: 0.000663 AC: 40 AN: 60370

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

African (AFR) AF: 0.0156 AC: 648 AN: 41576

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00184 Hom.: 4

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 v4.9

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
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.16
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.010
Sift	Benign	0.17	T
Sift4G	Benign	0.43	T
Polyphen		0.091	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

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