17-28631513-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014680.5(BLTP2):c.4265C>T(p.Thr1422Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000706 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.000068 (0 hom.)
• Consequence: BLTP2 NM_014680.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

Genes affected

BLTP2 (HGNC:28960): (bridge-like lipid transfer protein family member 2) This gene was initially characterized in human as having high expression levels in breast carcinomas and breast cancer cell lines. This gene also has increased expression in prostrate cancer cells relative to normal prostrate tissues. Expression of this gene is negatively regulated by direct binding of the microRNA miR-195 to its 3' UTR. miR-195 has been shown to modulate the invasiveness of prostrate cancer cells and xenograft metastases by downgrading expression of this gene. In mouse, the protein encoded by this gene was identified as an antigen on acute monocytic leukemia cells. In human, alternative splicing results in multiple transcript variants encoding distinct isoforms; some of these isoforms are predicted to contain an RNA pol II promoter FMP27 protein domain and a Golgi-body-localization APT1 domain. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BLTP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.21090224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLTP2	NM_014680.5	c.4265C>T	p.Thr1422Ile	missense_variant	23/39	ENST00000528896.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLTP2	ENST00000528896.7	c.4265C>T	p.Thr1422Ile	missense_variant	23/39	1	NM_014680.5	P1
BLTP2	ENST00000389003.7	c.3836C>T	p.Thr1279Ile	missense_variant	23/39	5
BLTP2	ENST00000577261.1	c.833C>T	p.Thr278Ile	missense_variant	6/6	3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251426 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135876

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000701 AC XY: 51 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000638

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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

Jun 06, 2023

The c.4265C>T (p.T1422I) alteration is located in exon 23 (coding exon 23) of the KIAA0100 gene. This alteration results from a C to T substitution at nucleotide position 4265, causing the threonine (T) at amino acid position 1422 to be replaced by an isoleucine (I). 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	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.3	D;D;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.0080	D;D;D;.
Polyphen		0.97	D;.;.;.
Vest4		0.66
MutPred		0.31		Loss of disorder (P = 0.016);.;.;.;
MVP		0.47
MPC		0.41
ClinPred		0.17	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.53

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: rs576143414; hg19: chr17-26958531;