rs1051597475

Positions:

• chr4-122226815-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_001384125.1(BLTP1):​c.2902C>T​(p.Arg968Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BLTP1 NM_001384125.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.99

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]

BLTP1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BLTP1. . Gene score misZ 6.0015 (greater than the threshold 3.09). Trascript score misZ 7.6647 (greater than threshold 3.09). GenCC has associacion of gene with Alkuraya-Kucinskas syndrome.
• PP5: Variant 4-122226815-C-T is Pathogenic according to our data. Variant chr4-122226815-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 487550.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-122226815-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLTP1	NM_001384125.1	c.2902C>T	p.Arg968Cys	missense_variant	24/88	ENST00000679879.1	NP_001371054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLTP1	ENST00000679879.1	c.2902C>T	p.Arg968Cys	missense_variant	24/88		NM_001384125.1	ENSP00000505357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456852 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this missense variant does not alter protein structure/function, but splice predictors indicate that the variant may lead to abnormal gene splicing; This variant is associated with the following publications: (PMID: 29290337) -

Alkuraya-Kucinskas syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.020	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.065	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.46		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.55
MPC		0.65
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.52		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1051597475; hg19: chr4-123147970; COSMIC: COSV52690863;