6-26451798-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006994.5(BTN3A3):c.1142G>A(p.Arg381His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: BTN3A3 NM_006994.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.58

Genes affected

BTN3A3 (HGNC:1140): (butyrophilin subfamily 3 member A3) The butyrophilin (BTN) genes are a group of major histocompatibility complex (MHC)-associated genes that encode type I membrane proteins with 2 extracellular immunoglobulin (Ig) domains and an intracellular B30.2 (PRYSPRY) domain. Three subfamilies of human BTN genes are located in the MHC class I region: the single-copy BTN1A1 gene (MIM 601610) and the BTN2 (e.g., BTN2A1; MIM 613590) and BTN3 (e.g., BNT3A3) genes, which have undergone tandem duplication, resulting in 3 copies of each (summary by Smith et al., 2010 [PubMed 20208008]).[supplied by OMIM, Nov 2010]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06723988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTN3A3	NM_006994.5	c.1142G>A	p.Arg381His	missense_variant	11/11	ENST00000244519.7
BTN3A3	NM_197974.3	c.995G>A	p.Arg332His	missense_variant	10/10
BTN3A3	NM_001242803.2	c.512G>A	p.Arg171His	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTN3A3	ENST00000244519.7	c.1142G>A	p.Arg381His	missense_variant	11/11	1	NM_006994.5	P1
	ENST00000707189.1	n.1000-101389G>A		intron_variant, non_coding_transcript_variant
	ENST00000707191.1	n.1001-80907G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251484 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135916

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46 AN XY: 727180

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74460

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.1142G>A (p.R381H) alteration is located in exon 11 (coding exon 9) of the BTN3A3 gene. This alteration results from a G to A substitution at nucleotide position 1142, causing the arginine (R) at amino acid position 381 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.024
Dann	Benign	0.90
DEOGEN2	Benign	0.045	T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.18	T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.40	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.86	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.081	B;.;.
Vest4		0.069
MVP		0.14
MPC		0.042
ClinPred		0.010	T
GERP RS		-5.8
Varity_R		0.047
gMVP		0.12

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: rs147489251; hg19: chr6-26452026;