rs61733139

Positions:

• chr4-99583409-G-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.285G>C​(p.Gln95His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,613,172 control chromosomes in the GnomAD database, including 2,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (196 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2366 hom.)
• Consequence: MTTP NM_001386140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.112

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021850765).
• BP6: Variant 4-99583409-G-C is Benign according to our data. Variant chr4-99583409-G-C is described in ClinVar as [Benign]. Clinvar id is 197124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99583409-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.285G>C	p.Gln95His	missense_variant	3/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4	c.285G>C	p.Gln95His	missense_variant	4/19		NP_000244.2
MTTP	NM_001300785.2	c.36G>C	p.Gln12His	missense_variant	3/18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.285G>C	p.Gln95His	missense_variant	3/18	1	NM_001386140.1	ENSP00000265517.5

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7434 AN: 152074 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0535

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0405 AC: 10068 AN: 248844 Hom.: 277 AF XY: 0.0413 AC XY: 5567 AN XY: 134932

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.0307

Gnomad ASJ exome AF: 0.0497

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0356

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0542

Gnomad OTH exome AF: 0.0473

GnomAD4 exome AF: 0.0535 AC: 78176 AN: 1460980 Hom.: 2366 Cov.: 31 AF XY: 0.0528 AC XY: 38383 AN XY: 726774

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.0320

Gnomad4 ASJ exome AF: 0.0483

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0159

Gnomad4 NFE exome AF: 0.0601

Gnomad4 OTH exome AF: 0.0502

GnomAD4 genome AF: 0.0489 AC: 7436 AN: 152192 Hom.: 196 Cov.: 32 AF XY: 0.0474 AC XY: 3528 AN XY: 74404

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.0534

Gnomad4 ASJ AF: 0.0519

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0381

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0563

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0535 Hom.: 166

Bravo AF: 0.0509

TwinsUK AF: 0.0666 AC: 247

ALSPAC AF: 0.0610 AC: 235

ESP6500AA AF: 0.0511 AC: 225

ESP6500EA AF: 0.0547 AC: 470

ExAC AF: 0.0404 AC: 4904

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0561

EpiControl AF: 0.0618

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2021	Variant summary: MTTP c.285G>C (p.Gln95His) results in a non-conservative amino acid change located in the Lipid transport protein, N-terminal domain (IPR001747) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.04 in 248844 control chromosomes in the gnomAD database, including 277 homozygotes. The observed variant frequency is approximately 38- fold the estimated maximal expected allele frequency for a pathogenic variant in MTTP causing Abetalipoproteinaemia (Bassen-Kornzweig Syndrome) phenotype (0.0011), strongly suggesting that the variant is benign. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2014	- -

Abetalipoproteinaemia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;.;T;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.63	T;T;.;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;.;L;L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.61	N;N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.11	T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.0010	.;B;B;B;.
Vest4		0.033, 0.018, 0.040
MutPred		0.33		.;Gain of glycosylation at S127 (P = 0.0253);.;.;.;
MPC		0.23
ClinPred		0.0070	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.43

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: rs61733139; hg19: chr4-100504566; COSMIC: COSV55509328; COSMIC: COSV55509328;