chr4-99597126-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000248676 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 129629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99597126-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.969T>C	p.Ala323Ala	synonymous_variant	Exon 8 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4	c.969T>C	p.Ala323Ala	synonymous_variant	Exon 9 of 19		NP_000244.2
MTTP	NM_001300785.2	c.720T>C	p.Ala240Ala	synonymous_variant	Exon 8 of 18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.969T>C	p.Ala323Ala	synonymous_variant	Exon 8 of 18	1	NM_001386140.1	ENSP00000265517.5
MTTP	ENST00000457717.6	c.969T>C	p.Ala323Ala	synonymous_variant	Exon 9 of 19	5		ENSP00000400821.1
MTTP	ENST00000511045.6	c.720T>C	p.Ala240Ala	synonymous_variant	Exon 8 of 18	2		ENSP00000427679.2
ENSG00000248676	ENST00000508578.1	n.129-1485A>G		intron_variant	Intron 2 of 3	5

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

GnomAD3 exomes AF: 0.0971 AC: 24389 AN: 251068 Hom.: 1575 AF XY: 0.0983 AC XY: 13335 AN XY: 135672

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 SAS exome AF: 0.0764

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

Gnomad4 AFR exome AF: 0.0864

Gnomad4 AMR exome AF: 0.0743

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.0772

Gnomad4 FIN exome AF: 0.0556

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.119

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

Gnomad4 AFR AF: 0.0864

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0670

Gnomad4 FIN AF: 0.0548

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.119

Alfa AF: 0.128 Hom.: 770

Bravo AF: 0.107

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.128

ClinVar

Significance: Benign

Submissions summary: Benign:7

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Apr 12, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Abetalipoproteinaemia Benign:2

Nov 21, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.15
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs17533489; hg19: chr4-100518283;