4-122186116-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BS1_Supporting

The NM_001384125.1(BLTP1):c.439C>T(p.Arg147Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,612,128 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: BLTP1 NM_001384125.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

Genes affected

BLTP1 (HGNC:26953): (bridge-like lipid transfer protein family member 1) This gene is located on the long arm of chromosome 4 in a region that is associated with susceptibility to celiac disease. The encoded protein is similar to a Chinese hamster protein that is associated with spermatocyte and adipocyte differentiation. The C-terminus of the protein is also similar to a Caenorhabditis elegans protein that plays a role in lipid storage. In mammals, this protein is thought to function in the regulation of epithelial growth and differentiation, and in tumor development. [provided by RefSeq, Oct 2009]

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, BLTP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3040641).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000026 (38/1460040) while in subpopulation EAS AF= 0.000607 (24/39558). AF 95% confidence interval is 0.000417. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLTP1	NM_001384125.1	c.439C>T	p.Arg147Cys	missense_variant	7/88	ENST00000679879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLTP1	ENST00000679879.1	c.439C>T	p.Arg147Cys	missense_variant	7/88		NM_001384125.1	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000724 AC: 18 AN: 248566 Hom.: 0 AF XY: 0.0000519 AC XY: 7 AN XY: 134922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000669

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1460040 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 726362

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000607

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.0000662 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alkuraya-Kucinskas syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.83	P;P
Vest4		0.57
MutPred		0.43		Gain of catalytic residue at L148 (P = 0.0135);Gain of catalytic residue at L148 (P = 0.0135);
MVP		0.67
MPC		1.1
ClinPred		0.25	T
GERP RS		4.9
Varity_R		0.17
gMVP		0.39

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: rs779054376; hg19: chr4-123107271; COSMIC: COSV52671864; COSMIC: COSV52671864;