4-99604358-T-G

Variant names:

• chr4-99604358-T-G
• rs3828542
• NM_001386140.1:c.1345-2390T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386140.1(MTTP):​c.1345-2390T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,076 control chromosomes in the GnomAD database, including 3,095 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3095 hom., cov: 31)
• Consequence: MTTP NM_001386140.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.212
• Publications: 3 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

ENSG00000248676 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.1345-2390T>G		intron_variant	Intron 10 of 17	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4	c.1345-2390T>G		intron_variant	Intron 11 of 18		NP_000244.2
MTTP	NM_001300785.2	c.1096-2390T>G		intron_variant	Intron 10 of 17		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.1345-2390T>G		intron_variant	Intron 10 of 17	1	NM_001386140.1	ENSP00000265517.5

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28280 AN: 151960 Hom.: 3093 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.0807

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.187

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

GnomAD4 genome AF: 0.186 AC: 28295 AN: 152076 Hom.: 3095 Cov.: 31 AF XY: 0.185 AC XY: 13746 AN XY: 74354

African (AFR) AF: 0.238 AC: 9854 AN: 41478

American (AMR) AF: 0.133 AC: 2035 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 736 AN: 3468

East Asian (EAS) AF: 0.441 AC: 2273 AN: 5150

South Asian (SAS) AF: 0.272 AC: 1314 AN: 4824

European-Finnish (FIN) AF: 0.0807 AC: 856 AN: 10610

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10681 AN: 67976

Other (OTH) AF: 0.188 AC: 396 AN: 2106

Alfa AF: 0.171 Hom.: 1116

Bravo AF: 0.192

Asia WGS AF: 0.287 AC: 1001 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.2
DANN	Benign	0.50
PhyloP100		0.21
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: rs3828542; hg19: chr4-100525515;