4-99574331-G-T

Variant names:

• chr4-99574331-G-T
• rs1800591
• NM_000253.4:c.-101-478G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000253.4(MTTP):​c.-101-478G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,084 control chromosomes in the GnomAD database, including 5,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (5385 hom., cov: 32)
• Consequence: MTTP NM_000253.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.279
• Publications: 56 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-99574331-G-T is Benign according to our data. Variant chr4-99574331-G-T is described in ClinVar as Benign. ClinVar VariationId is 1168852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000253.4. 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
	MTTP	NM_000253.4		c.-101-478G>T		intron	N/A	NP_000244.2
	MTTP	NM_001300785.2		c.-188-7574G>T		intron	N/A	NP_001287714.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTTP	ENST00000457717.6	TSL:5	c.-101-478G>T		intron	N/A	ENSP00000400821.1
	MTTP	ENST00000511045.6	TSL:2	c.-188-7574G>T		intron	N/A	ENSP00000427679.2
	MTTP	ENST00000511610.6	TSL:4	c.-101-478G>T		intron	N/A	ENSP00000422178.2

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39816 AN: 151966 Hom.: 5377 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.297

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.262 AC: 39847 AN: 152084 Hom.: 5385 Cov.: 32 AF XY: 0.261 AC XY: 19383 AN XY: 74366

African (AFR) AF: 0.278 AC: 11522 AN: 41462

American (AMR) AF: 0.237 AC: 3630 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1384 AN: 3472

East Asian (EAS) AF: 0.146 AC: 757 AN: 5172

South Asian (SAS) AF: 0.347 AC: 1670 AN: 4814

European-Finnish (FIN) AF: 0.190 AC: 2010 AN: 10576

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17700 AN: 67972

Other (OTH) AF: 0.298 AC: 630 AN: 2116

Alfa AF: 0.252 Hom.: 8062

Bravo AF: 0.261

Asia WGS AF: 0.290 AC: 1006 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.71
DANN	Benign	0.30
PhyloP100		-0.28
PromoterAI		-0.0046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800591; hg19: chr4-100495488;