rs17029215

chr4-99600648-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001386140.1(MTTP):c.1151A>C(p.Asp384Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,613,764 control chromosomes in the GnomAD database, including 2,338 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D384N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.070 (613 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1725 hom.)
• Consequence: MTTP NM_001386140.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.963

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013110638).
• BP6: Variant 4-99600648-A-C is Benign according to our data. Variant chr4-99600648-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 283193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99600648-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTTP	NM_001386140.1	c.1151A>C	p.Asp384Ala	missense_variant	9/18	ENST00000265517.10
MTTP	NM_000253.4	c.1151A>C	p.Asp384Ala	missense_variant	10/19
MTTP	NM_001300785.2	c.902A>C	p.Asp301Ala	missense_variant	9/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTTP	ENST00000265517.10	c.1151A>C	p.Asp384Ala	missense_variant	9/18	1	NM_001386140.1	P1
	ENST00000508578.1	n.129-5007T>G		intron_variant, non_coding_transcript_variant		5
MTTP	ENST00000457717.6	c.1151A>C	p.Asp384Ala	missense_variant	10/19	5		P1
MTTP	ENST00000511045.6	c.902A>C	p.Asp301Ala	missense_variant	9/18	2

Frequencies

GnomAD3 genomes AF: 0.0699 AC: 10637 AN: 152098 Hom.: 613 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0534

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.0650

GnomAD3 exomes AF: 0.0436 AC: 10959 AN: 251098 Hom.: 419 AF XY: 0.0417 AC XY: 5660 AN XY: 135700

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0510

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0288

Gnomad FIN exome AF: 0.0547

Gnomad NFE exome AF: 0.0378

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0426 AC: 62288 AN: 1461548 Hom.: 1725 Cov.: 31 AF XY: 0.0417 AC XY: 30307 AN XY: 727092

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.0352

Gnomad4 ASJ exome AF: 0.0523

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0304

Gnomad4 FIN exome AF: 0.0512

Gnomad4 NFE exome AF: 0.0408

Gnomad4 OTH exome AF: 0.0488

GnomAD4 genome AF: 0.0699 AC: 10647 AN: 152216 Hom.: 613 Cov.: 32 AF XY: 0.0679 AC XY: 5053 AN XY: 74428

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0481

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0275

Gnomad4 FIN AF: 0.0534

Gnomad4 NFE AF: 0.0375

Gnomad4 OTH AF: 0.0643

Alfa AF: 0.0441 Hom.: 449

Bravo AF: 0.0747

TwinsUK AF: 0.0394 AC: 146

ALSPAC AF: 0.0400 AC: 154

ESP6500AA AF: 0.155 AC: 683

ESP6500EA AF: 0.0393 AC: 338

ExAC AF: 0.0459 AC: 5567

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0424

EpiControl AF: 0.0445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -

Abetalipoproteinaemia Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 31, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2018	This variant is associated with the following publications: (PMID: 23475612, 20981092, 15910857, 27884173, 27487388, 30782561) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	12
Dann	Benign	0.87
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.65	T;.;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.025
MPC		0.29
ClinPred		0.0031	T
GERP RS		0.96
Varity_R		0.10
gMVP		0.22

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: rs17029215; hg19: chr4-100521805; COSMIC: COSV55505603;