dbSNP rs745075: MTTP:c.1989+27T>C (chr4-99611480-T-C) – 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.1989+27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,612,368 control chromosomes in the GnomAD database, including 11,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 995 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10279 hom. )

Consequence

MTTP
NM_001386140.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00

Publications

12 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=-0.83).

BP6

Variant 4-99611480-T-C is Benign according to our data. Variant chr4-99611480-T-C is described in ClinVar as Benign. ClinVar VariationId is 1260037.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.1989+27T>C	intron_variant	Intron 14 of 17	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.1989+27T>C	intron_variant	Intron 15 of 18		NP_000244.2	P55157-1
MTTP	NM_001300785.2 link	c.1740+27T>C	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.1989+27T>C		intron_variant	Intron 14 of 17	1	NM_001386140.1	ENSP00000265517.5		P55157-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15852

AN:

152072

Hom.:

994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0859

Gnomad AMI

AF:

0.341

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0668

Gnomad FIN

AF:

0.0547

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.121

GnomAD2 exomes

AF:

0.0971

AC:

24327

AN:

250594

AF XY:

0.0982

show subpopulations

Gnomad AFR exome

AF:

0.0845

Gnomad AMR exome

AF:

0.0705

Gnomad ASJ exome

AF:

0.279

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0531

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.112

AC:

164030

AN:

1460178

Hom.:

10279

Cov.:

AF XY:

0.112

AC XY:

81298

AN XY:

726504

show subpopulations

African (AFR)

AF:

0.0864

AC:

2889

AN:

33446

American (AMR)

AF:

0.0744

AC:

3326

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6974

AN:

26106

East Asian (EAS)

AF:

0.000328

AC:

AN:

39690

South Asian (SAS)

AF:

0.0772

AC:

6655

AN:

86226

European-Finnish (FIN)

AF:

0.0555

AC:

2958

AN:

53304

Middle Eastern (MID)

AF:

0.185

AC:

1063

AN:

5758

European-Non Finnish (NFE)

AF:

0.120

AC:

132988

AN:

1110606

Other (OTH)

AF:

0.119

AC:

7164

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

7415

14830

22246

29661

37076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4774

9548

14322

19096

23870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.104

AC:

15872

AN:

152190

Hom.:

995

Cov.:

AF XY:

0.103

AC XY:

7631

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0863

AC:

3584

AN:

41522

American (AMR)

AF:

0.107

AC:

1640

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

908

AN:

3466

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0669

AC:

322

AN:

4816

European-Finnish (FIN)

AF:

0.0547

AC:

580

AN:

10610

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8212

AN:

68008

Other (OTH)

AF:

0.120

AC:

253

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

699

1397

2096

2794

3493

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:

0.125

Hom.:

2540

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.0

(source)

DANN

Benign

0.59

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over