Genetic Variant BTNL3:p.Glu124Ala (chr5-180993134-A-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_197975.3(BTNL3):c.371A>C(p.Glu124Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,444,390 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000073 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000024 ( 8 hom. )

Consequence

BTNL3
NM_197975.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.297

Variant links:

Genes affected

BTNL3 (HGNC:1143): (butyrophilin like 3) Predicted to enable signaling receptor binding activity. Predicted to be involved in T cell receptor signaling pathway and regulation of cytokine production. Predicted to be integral component of membrane. Predicted to be active in external side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

BTNL3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18339676).

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTNL3	NM_197975.3 link	c.371A>C	p.Glu124Ala	missense_variant	Exon 2 of 8	ENST00000342868.7	NP_932079.1	Q6UXE8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTNL3	ENST00000342868.7 link	c.371A>C	p.Glu124Ala	missense_variant	Exon 2 of 8	1	NM_197975.3	ENSP00000341787.6		Q6UXE8-1

Frequencies

GnomAD3 genomes

AF:

0.00000731

AC:

AN:

136736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000168

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000206

AC:

AN:

194508

Hom.:

AF XY:

0.0000190

AC XY:

AN XY:

105100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.000221

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:

0.00

GnomAD4 exome

AF:

0.0000245

AC:

AN:

1307654

Hom.:

Cov.:

AF XY:

0.0000323

AC XY:

AN XY:

649970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000804

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.000164

GnomAD4 genome

AF:

0.00000731

AC:

AN:

136736

Hom.:

Cov.:

AF XY:

0.0000150

AC XY:

AN XY:

66464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000168

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000180

AC:

Asia WGS

AF:

0.000302

AC:

AN:

3326

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371A>C (p.E124A) alteration is located in exon 2 (coding exon 2) of the BTNL3 gene. This alteration results from a A to C substitution at nucleotide position 371, causing the glutamic acid (E) at amino acid position 124 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.8

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.50

M_CAP

Benign

0.0094

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.1

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.064

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.018

Polyphen

0.58

Vest4

0.32

MutPred

0.58

Loss of disorder (P = 0.1386);

MVP

0.37

MPC

1.0

ClinPred

0.38

GERP RS

1.6

Varity_R

0.13

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over