rs17533489

Variant names:

• chr4-99597126-T-C
• rs17533489
• NM_001386140.1:c.969T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001386140.1(MTTP):​c.969T>C​(p.Ala323Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,882 control chromosomes in the GnomAD database, including 11,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (998 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10290 hom.)
• Consequence: MTTP NM_001386140.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.07
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-99597126-T-C is Benign according to our data. Variant chr4-99597126-T-C is described in ClinVar as Benign. ClinVar VariationId is 129629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• 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.969T>C	p.Ala323Ala	synonymous	Exon 8 of 18	NP_001373069.1	P55157-1
	MTTP	NM_000253.4		c.969T>C	p.Ala323Ala	synonymous	Exon 9 of 19	NP_000244.2	P55157-1
	MTTP	NM_001300785.2		c.720T>C	p.Ala240Ala	synonymous	Exon 8 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.969T>C	p.Ala323Ala	synonymous	Exon 8 of 18	ENSP00000265517.5	P55157-1
	MTTP	ENST00000457717.6	TSL:5	c.969T>C	p.Ala323Ala	synonymous	Exon 9 of 19	ENSP00000400821.1	P55157-1
	MTTP	ENST00000511045.6	TSL:2	c.720T>C	p.Ala240Ala	synonymous	Exon 8 of 18	ENSP00000427679.2	E9PBP6

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15852 AN: 152072 Hom.: 997 Cov.: 32

Gnomad AFR AF: 0.0860

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0669

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.0971 AC: 24389 AN: 251068 AF XY: 0.0983

Gnomad AFR exome AF: 0.0845

Gnomad AMR exome AF: 0.0704

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.112 AC: 164426 AN: 1461692 Hom.: 10290 Cov.: 33 AF XY: 0.112 AC XY: 81465 AN XY: 727150

African (AFR) AF: 0.0864 AC: 2892 AN: 33468

American (AMR) AF: 0.0743 AC: 3324 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6985 AN: 26128

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39694

South Asian (SAS) AF: 0.0772 AC: 6661 AN: 86254

European-Finnish (FIN) AF: 0.0556 AC: 2968 AN: 53410

Middle Eastern (MID) AF: 0.185 AC: 1065 AN: 5766

European-Non Finnish (NFE) AF: 0.120 AC: 133331 AN: 1111864

Other (OTH) AF: 0.119 AC: 7187 AN: 60394

GnomAD4 genome AF: 0.104 AC: 15872 AN: 152190 Hom.: 998 Cov.: 32 AF XY: 0.102 AC XY: 7626 AN XY: 74404

African (AFR) AF: 0.0864 AC: 3589 AN: 41530

American (AMR) AF: 0.107 AC: 1639 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0670 AC: 323 AN: 4824

European-Finnish (FIN) AF: 0.0548 AC: 581 AN: 10608

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

European-Non Finnish (NFE) AF: 0.121 AC: 8207 AN: 67982

Other (OTH) AF: 0.119 AC: 252 AN: 2110

Alfa AF: 0.125 Hom.: 1020

Bravo AF: 0.107

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.128

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Abetalipoproteinaemia (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.15
DANN	Benign	0.47
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs17533489; hg19: chr4-100518283;