6-26445944-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.674C>T(p.Ser225Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: BTN3A3 NM_006994.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.30

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=0.13242689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTN3A3	NM_006994.5	c.674C>T	p.Ser225Phe	missense_variant	5/11	ENST00000244519.7
BTN3A3	NM_197974.3	c.548C>T	p.Ser183Phe	missense_variant	5/10
BTN3A3	NM_001242803.2	c.307+1640C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTN3A3	ENST00000244519.7	c.674C>T	p.Ser225Phe	missense_variant	5/11	1	NM_006994.5	P1
	ENST00000707189.1	n.1000-107243C>T		intron_variant, non_coding_transcript_variant
	ENST00000707191.1	n.1001-86761C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251422 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135882

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000622 AC: 91 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74436

Gnomad4 AFR AF: 0.0000482

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: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000997 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

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

Aug 28, 2023

The c.674C>T (p.S225F) alteration is located in exon 5 (coding exon 3) of the BTN3A3 gene. This alteration results from a C to T substitution at nucleotide position 674, causing the serine (S) at amino acid position 225 to be replaced by a phenylalanine (F). 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	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Benign	0.075
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Uncertain	0.036	D;T;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.097
MVP		0.87
MPC		0.19
ClinPred		0.43	T
GERP RS		1.2
Varity_R		0.12
gMVP		0.039

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: rs200625612; hg19: chr6-26446172; COSMIC: COSV55071353; COSMIC: COSV55071353;