4-122309365-G-C

Position:

• chr4-122309365-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001384125.1(BLTP1):​c.10153G>C​(p.Gly3385Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLTP1 NM_001384125.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.88

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 Likely_pathogenic. Variant got 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• PP5: Variant 4-122309365-G-C is Pathogenic according to our data. Variant chr4-122309365-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 487551.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-122309365-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLTP1	NM_001384125.1	c.10153G>C	p.Gly3385Arg	missense_variant	59/88	ENST00000679879.1	NP_001371054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLTP1	ENST00000679879.1	c.10153G>C	p.Gly3385Arg	missense_variant	59/88		NM_001384125.1	ENSP00000505357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.2	D;D;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.49		Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;.;
MVP		0.60
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554059454; hg19: chr4-123230520;