4-122309365-G-C

Variant names:

• chr4-122309365-G-C
• rs1554059454
• NM_001384125.1:c.10153G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Alkuraya-Kucinskas syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 487551.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384125.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLTP1	NM_001384125.1	MANE Select	c.10153G>C	p.Gly3385Arg	missense	Exon 59 of 88	NP_001371054.1
	BLTP1	NM_015312.4		c.10153G>C	p.Gly3385Arg	missense	Exon 57 of 84	NP_056127.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLTP1	ENST00000679879.1	MANE Select	c.10153G>C	p.Gly3385Arg	missense	Exon 59 of 88	ENSP00000505357.1
	BLTP1	ENST00000388738.8	TSL:1	c.10102G>C	p.Gly3368Arg	missense	Exon 58 of 85	ENSP00000373390.4
	BLTP1	ENST00000419325.5	TSL:1	c.4024G>C	p.Gly1342Arg	missense	Exon 21 of 28	ENSP00000393219.1

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

Jan 11, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.49		Loss of loop (P = 0.0203)
MVP		0.60
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.017	Neutral
Varity_R		0.86
gMVP		0.99
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554059454; hg19: chr4-123230520;