4-99574660-T-C

Variant names:

• chr4-99574660-T-C
• rs1800804
• NM_000253.4:c.-101-149T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000253.4(MTTP):​c.-101-149T>C 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 756,350 control chromosomes in the GnomAD database, including 27,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5371 hom., cov: 32)
  • Exomes 𝑓: 0.26 (21840 hom.)
• Consequence: MTTP NM_000253.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.766
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-99574660-T-C is Benign according to our data. Variant chr4-99574660-T-C is described in ClinVar as Benign. ClinVar VariationId is 1168853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTTP	NM_000253.4	c.-101-149T>C		intron_variant	Intron 1 of 18		NP_000244.2
MTTP	NM_001300785.2	c.-188-7245T>C		intron_variant	Intron 1 of 17		NP_001287714.2
MTTP	NM_001386140.1	c.-250T>C		upstream_gene_variant		ENST00000265517.10	NP_001373069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.-250T>C		upstream_gene_variant		1	NM_001386140.1	ENSP00000265517.5

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39787 AN: 151934 Hom.: 5363 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.296

GnomAD4 exome AF: 0.263 AC: 158707 AN: 604296 Hom.: 21840 Cov.: 8 AF XY: 0.267 AC XY: 84983 AN XY: 318270

African (AFR) AF: 0.290 AC: 4449 AN: 15332

American (AMR) AF: 0.180 AC: 4778 AN: 26554

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 6662 AN: 16750

East Asian (EAS) AF: 0.152 AC: 4407 AN: 28986

South Asian (SAS) AF: 0.340 AC: 19289 AN: 56786

European-Finnish (FIN) AF: 0.191 AC: 5404 AN: 28336

Middle Eastern (MID) AF: 0.340 AC: 1015 AN: 2988

European-Non Finnish (NFE) AF: 0.262 AC: 104275 AN: 397886

Other (OTH) AF: 0.275 AC: 8428 AN: 30678

GnomAD4 genome AF: 0.262 AC: 39818 AN: 152054 Hom.: 5371 Cov.: 32 AF XY: 0.260 AC XY: 19353 AN XY: 74302

African (AFR) AF: 0.278 AC: 11504 AN: 41446

American (AMR) AF: 0.237 AC: 3627 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1384 AN: 3466

East Asian (EAS) AF: 0.146 AC: 754 AN: 5176

South Asian (SAS) AF: 0.347 AC: 1672 AN: 4816

European-Finnish (FIN) AF: 0.190 AC: 2012 AN: 10576

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

European-Non Finnish (NFE) AF: 0.260 AC: 17695 AN: 67974

Other (OTH) AF: 0.297 AC: 626 AN: 2108

Alfa AF: 0.264 Hom.: 7468

Bravo AF: 0.261

Asia WGS AF: 0.290 AC: 1007 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17854051)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.34
DANN	Benign	0.36
PhyloP100		-0.77
PromoterAI		-0.028	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: rs1800804; hg19: chr4-100495817;