4-99581979-C-G

Position:

• chr4-99581979-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001300785.2(MTTP):​c.-114C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,614,112 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (322 hom.)
• Consequence: MTTP NM_001300785.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.29

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=0.00479275).
• BP6: Variant 4-99581979-C-G is Benign according to our data. Variant chr4-99581979-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 347020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99581979-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0138 (2097/152274) while in subpopulation SAS AF= 0.0349 (168/4818). AF 95% confidence interval is 0.0306. There are 22 homozygotes in gnomad4. There are 1088 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.136C>G	p.Arg46Gly	missense_variant	2/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_001300785.2	c.-114C>G		5_prime_UTR_premature_start_codon_gain_variant	2/18		NP_001287714.2
MTTP	NM_000253.4	c.136C>G	p.Arg46Gly	missense_variant	3/19		NP_000244.2
MTTP	NM_001300785.2	c.-114C>G		5_prime_UTR_variant	2/18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.136C>G	p.Arg46Gly	missense_variant	2/18	1	NM_001386140.1	ENSP00000265517.5

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2098 AN: 152156 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0187 AC: 4696 AN: 251466 Hom.: 68 AF XY: 0.0202 AC XY: 2750 AN XY: 135904

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00755

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0405

Gnomad FIN exome AF: 0.0347

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0176 AC: 25710 AN: 1461838 Hom.: 322 Cov.: 31 AF XY: 0.0183 AC XY: 13325 AN XY: 727222

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00745

Gnomad4 ASJ exome AF: 0.00647

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0394

Gnomad4 FIN exome AF: 0.0308

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0138 AC: 2097 AN: 152274 Hom.: 22 Cov.: 32 AF XY: 0.0146 AC XY: 1088 AN XY: 74448

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0349

Gnomad4 FIN AF: 0.0327

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0125 Hom.: 8

Bravo AF: 0.0110

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0176 AC: 151

ExAC AF: 0.0189 AC: 2295

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2019	This variant is associated with the following publications: (PMID: 27487388, 27884173, 20592474, 25525159) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	MTTP: BP4, BS1, BS2 -

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. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -

not specified Benign:2

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;.;T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.64	T;T;.;T;T
MetaRNN	Benign	0.0048	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;L;L;L
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.0	N;N;N;N;D
REVEL	Benign	0.089
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.0010	.;B;B;B;.
Vest4		0.083, 0.072, 0.070, 0.19
MPC		0.30
ClinPred		0.0077	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.42

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: rs141736123; hg19: chr4-100503136;