Genetic Variant NM_001386140.1:c.1990-157C>T (chr4-99612756-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001386140.1(MTTP):c.1990-157C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,180 control chromosomes in the GnomAD database, including 1,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1003 hom., cov: 32)

Consequence

MTTP
NM_001386140.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.62

Publications

2 publications found

Variant links:

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]

MTTP Gene-Disease associations (from GenCC):

abetalipoproteinemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia, G2P

MTTP links:

ENSG00000248676 (HGNC:):

ENSG00000248676 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 4-99612756-C-T is Benign according to our data. Variant chr4-99612756-C-T is described in ClinVar as Benign. ClinVar VariationId is 1295320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MTTP	NM_001386140.1 link	c.1990-157C>T	intron_variant	Intron 14 of 17	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.1990-157C>T	intron_variant	Intron 15 of 18		NP_000244.2	P55157-1
MTTP	NM_001300785.2 link	c.1741-157C>T	intron_variant	Intron 14 of 17		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.1990-157C>T		intron_variant	Intron 14 of 17	1	NM_001386140.1	ENSP00000265517.5		P55157-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15871

AN:

152062

Hom.:

1002

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0860

Gnomad AMI

AF:

0.341

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0669

Gnomad FIN

AF:

0.0546

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.122

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.104

AC:

15891

AN:

152180

Hom.:

1003

Cov.:

AF XY:

0.103

AC XY:

7636

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0864

AC:

3587

AN:

41506

American (AMR)

AF:

0.108

AC:

1646

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

909

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0670

AC:

323

AN:

4824

European-Finnish (FIN)

AF:

0.0546

AC:

579

AN:

10602

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8220

AN:

68010

Other (OTH)

AF:

0.121

AC:

255

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

687

1375

2062

2750

3437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.108

Hom.:

302

Bravo

AF:

0.108

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.24

(source)

DANN

Benign

0.54

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over