4-99574660-T-C

Variant summary

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

The NM_000253.4(MTTP):c.-101-149T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 756,350 control chromosomes in the GnomAD database, including 27,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5371 hom., cov: 32)
  • Exomes 𝑓: 0.26 (21840 hom.)
• Consequence: MTTP NM_000253.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.766

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 (BayesDel_noAF=-0.83).
• BP6: Variant 4-99574660-T-C is Benign according to our data. Variant chr4-99574660-T-C is described in ClinVar as [Benign]. Clinvar id is 1168853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99574660-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTTP	NM_000253.4	c.-101-149T>C		intron_variant
MTTP	NM_001300785.2	c.-188-7245T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTTP	ENST00000457717.6	c.-101-149T>C		intron_variant		5		P1
MTTP	ENST00000505094.6	c.-189+3795T>C		intron_variant		4
MTTP	ENST00000511045.6	c.-188-7245T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39787 AN: 151934 Hom.: 5363 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.296

GnomAD4 exome AF: 0.263 AC: 158707 AN: 604296 Hom.: 21840 Cov.: 8 AF XY: 0.267 AC XY: 84983 AN XY: 318270

Gnomad4 AFR exome AF: 0.290

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.262 AC: 39818 AN: 152054 Hom.: 5371 Cov.: 32 AF XY: 0.260 AC XY: 19353 AN XY: 74302

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.297

Alfa AF: 0.263 Hom.: 5362

Bravo AF: 0.261

Asia WGS AF: 0.290 AC: 1007 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2019	This variant is associated with the following publications: (PMID: 17854051) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.34
Dann	Benign	0.36

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: rs1800804; hg19: chr4-100495817;