4-99574904-G-A

Position:

• chr4-99574904-G-A

Variant summary

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

The NM_001386140.1(MTTP):​c.-6G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,614,122 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: MTTP NM_001386140.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.812

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=-0.82).
• BP6: Variant 4-99574904-G-A is Benign according to our data. Variant chr4-99574904-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99574904-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00263 (401/152286) while in subpopulation NFE AF= 0.0035 (238/68016). AF 95% confidence interval is 0.00313. There are 4 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTTP	NM_001386140.1	c.-6G>A		5_prime_UTR_variant	1/18	ENST00000265517.10
MTTP	NM_000253.4	c.-6G>A		5_prime_UTR_variant	2/19
MTTP	NM_001300785.2	c.-188-7001G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTTP	ENST00000265517.10	c.-6G>A		5_prime_UTR_variant	1/18	1	NM_001386140.1	P1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152168 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00247 AC: 622 AN: 251454 Hom.: 2 AF XY: 0.00259 AC XY: 352 AN XY: 135910

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00970

Gnomad NFE exome AF: 0.00313

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00242 AC: 3534 AN: 1461836 Hom.: 6 Cov.: 31 AF XY: 0.00240 AC XY: 1748 AN XY: 727218

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00867

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152286 Hom.: 4 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74464

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00316 Hom.: 0

Bravo AF: 0.00153

EpiCase AF: 0.00294

EpiControl AF: 0.00213

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Abetalipoproteinaemia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MTTP: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2024	See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.6
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs41275707; hg19: chr4-100496061;