6-26444110-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006994.5(BTN3A3):c.239C>T(p.Ala80Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,738 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (1 hom.)
• Consequence: BTN3A3 NM_006994.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.57

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11789039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTN3A3	NM_006994.5	c.239C>T	p.Ala80Val	missense_variant	4/11	ENST00000244519.7
BTN3A3	NM_197974.3	c.113C>T	p.Ala38Val	missense_variant	4/10
BTN3A3	NM_001242803.2	c.113C>T	p.Ala38Val	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTN3A3	ENST00000244519.7	c.239C>T	p.Ala80Val	missense_variant	4/11	1	NM_006994.5	P1
	ENST00000707189.1	n.1000-109077C>T		intron_variant, non_coding_transcript_variant
	ENST00000707191.1	n.1001-88595C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000441

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 250948 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000972 AC: 142 AN: 1461588 Hom.: 1 Cov.: 32 AF XY: 0.000111 AC XY: 81 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000107 AC: 13

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

Feb 27, 2023

The c.239C>T (p.A80V) alteration is located in exon 4 (coding exon 2) of the BTN3A3 gene. This alteration results from a C to T substitution at nucleotide position 239, causing the alanine (A) at amino acid position 80 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	5.0
Dann	Uncertain	0.99
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.21	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.011	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T
Polyphen		0.33	.;.;B;.;.;.;.;.;.
Vest4		0.16, 0.17
MutPred		0.57		Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;.;
MVP		0.61
MPC		2.6
ClinPred		0.080	T
GERP RS		-2.4
Varity_R		0.13
gMVP		0.085

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs774008732; hg19: chr6-26444338; COSMIC: COSV55072546; COSMIC: COSV55072546;