6-26413363-A-G

Variant summary

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

The NM_007048.6(BTN3A1):c.1213A>G(p.Lys405Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,614,018 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 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: BTN3A1 NM_007048.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.484

Genes affected

BTN3A1 (HGNC:1138): (butyrophilin subfamily 3 member A1) 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., BNT3A1) 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=0.067612946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTN3A1	NM_007048.6	c.1213A>G	p.Lys405Glu	missense_variant	10/10	ENST00000289361.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTN3A1	ENST00000289361.11	c.1213A>G	p.Lys405Glu	missense_variant	10/10	1	NM_007048.6	P1
	ENST00000707189.1	n.1000-139824A>G		intron_variant, non_coding_transcript_variant
	ENST00000707191.1	n.1001-119342A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 251408 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135862

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000397 AC XY: 289 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000491

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74312

Gnomad4 AFR AF: 0.0000724

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: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000478 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000600

EpiControl AF: 0.000296

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

Jul 13, 2021

The c.1213A>G (p.K405E) alteration is located in exon 10 (coding exon 9) of the BTN3A1 gene. This alteration results from a A to G substitution at nucleotide position 1213, causing the lysine (K) at amino acid position 405 to be replaced by a glutamic acid (E). 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	0.22
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0025	T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.80	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.15
Sift	Benign	0.033	D;D
Sift4G	Benign	1.0	T;T
Polyphen		1.0	D;.
Vest4		0.057
MVP		0.69
MPC		0.16
ClinPred		0.039	T
GERP RS		-3.2
Varity_R		0.14
gMVP		0.054

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: rs143476765; hg19: chr6-26413591;