rs199422221

Positions:

• chr4-99619094-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001386140.1(MTTP):​c.2338A>T​(p.Asn780Tyr) 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: MTTP NM_001386140.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.53

Genes affected

MTTP (HGNC:7467): (microsomal triglyceride transfer protein) MTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein. Protein disulfide isomerase (PDI) completes the heterodimeric microsomal triglyceride transfer protein, which has been shown to play a central role in lipoprotein assembly. Mutations in MTP can cause abetalipoproteinemia. [provided by RefSeq, Jul 2008]

ENSG00000248676 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 4-99619094-A-T is Pathogenic according to our data. Variant chr4-99619094-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 14240.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-99619094-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.2338A>T	p.Asn780Tyr	missense_variant	16/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4	c.2338A>T	p.Asn780Tyr	missense_variant	17/19		NP_000244.2
MTTP	NM_001300785.2	c.2089A>T	p.Asn697Tyr	missense_variant	16/18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.2338A>T	p.Asn780Tyr	missense_variant	16/18	1	NM_001386140.1	ENSP00000265517.5
MTTP	ENST00000457717.6	c.2338A>T	p.Asn780Tyr	missense_variant	17/19	5		ENSP00000400821.1
MTTP	ENST00000511045.6	c.2089A>T	p.Asn697Tyr	missense_variant	16/18	2		ENSP00000427679.2
ENSG00000248676	ENST00000508578.1	n.128+1793T>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Abetalipoproteinaemia Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2000	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.63		Gain of sheet (P = 0.0028);.;.;
MVP		0.89
MPC		0.83
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.56

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: rs199422221; hg19: chr4-100540251;