rs199422221

Variant names:

• chr4-99619094-A-T
• rs199422221
• NM_001386140.1:c.2338A>T

Variant summary

Our verdict is Uncertain significance. The variant received 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). Synonymous variant affecting the same amino acid position (i.e. N780N) has been classified as Likely benign.

• 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
• Publications: 9 publications found

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]

MTTP Gene-Disease associations (from GenCC):

• abetalipoproteinemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000248676 (HGNC:54189):

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, 0.845
• PP5: Variant 4-99619094-A-T is Pathogenic according to our data. Variant chr4-99619094-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14240.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386140.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTTP	NM_001386140.1	MANE Select	c.2338A>T	p.Asn780Tyr	missense	Exon 16 of 18	NP_001373069.1	P55157-1
	MTTP	NM_000253.4		c.2338A>T	p.Asn780Tyr	missense	Exon 17 of 19	NP_000244.2	P55157-1
	MTTP	NM_001300785.2		c.2089A>T	p.Asn697Tyr	missense	Exon 16 of 18	NP_001287714.2	E9PBP6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTTP	ENST00000265517.10	TSL:1 MANE Select	c.2338A>T	p.Asn780Tyr	missense	Exon 16 of 18	ENSP00000265517.5	P55157-1
	MTTP	ENST00000457717.6	TSL:5	c.2338A>T	p.Asn780Tyr	missense	Exon 17 of 19	ENSP00000400821.1	P55157-1
	MTTP	ENST00000511045.6	TSL:2	c.2089A>T	p.Asn697Tyr	missense	Exon 16 of 18	ENSP00000427679.2	E9PBP6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Abetalipoproteinaemia (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	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
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199422221; hg19: chr4-100540251;