rs1491246

Variant names:

• chr4-99613325-A-T
• rs1491246
• NM_001386140.1:c.2217+185A>T

Variant summary

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

The NM_001386140.1(MTTP):​c.2217+185A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,180 control chromosomes in the GnomAD database, including 1,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.10 (1000 hom., cov: 32)
• Consequence: MTTP NM_001386140.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0870
• 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000248676 (HGNC:54189):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 4-99613325-A-T is Benign according to our data. Variant chr4-99613325-A-T is described in ClinVar as Benign. ClinVar VariationId is 1235879.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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.2217+185A>T		intron	N/A	NP_001373069.1	P55157-1
	MTTP	NM_000253.4		c.2217+185A>T		intron	N/A	NP_000244.2	P55157-1
	MTTP	NM_001300785.2		c.1968+185A>T		intron	N/A	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.2217+185A>T		intron	N/A	ENSP00000265517.5	P55157-1
	MTTP	ENST00000457717.6	TSL:5	c.2217+185A>T		intron	N/A	ENSP00000400821.1	P55157-1
	MTTP	ENST00000511045.6	TSL:2	c.1968+185A>T		intron	N/A	ENSP00000427679.2	E9PBP6

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15864 AN: 152062 Hom.: 999 Cov.: 32

Gnomad AFR AF: 0.0861

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0666

Gnomad FIN AF: 0.0547

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.104 AC: 15884 AN: 152180 Hom.: 1000 Cov.: 32 AF XY: 0.103 AC XY: 7632 AN XY: 74402

African (AFR) AF: 0.0865 AC: 3591 AN: 41518

American (AMR) AF: 0.108 AC: 1642 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0667 AC: 322 AN: 4828

European-Finnish (FIN) AF: 0.0547 AC: 579 AN: 10590

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8215 AN: 68006

Other (OTH) AF: 0.120 AC: 254 AN: 2110

Alfa AF: 0.113 Hom.: 129

Bravo AF: 0.107

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

ClinVar submissions

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	-0.95
CADD	Benign	3.6
DANN	Benign	0.78
PhyloP100		-0.087
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: rs1491246; hg19: chr4-100534482;