chr4-99611480-T-C

Variant names:

• chr4-99611480-T-C
• rs745075
• NM_001386140.1:c.1989+27T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 12 publications found

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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000248676 (HGNC:54189):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386140.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTTP	NM_001386140.1	MANE Select	c.1989+27T>C		intron	N/A	NP_001373069.1	P55157-1
	MTTP	NM_000253.4		c.1989+27T>C		intron	N/A	NP_000244.2	P55157-1
	MTTP	NM_001300785.2		c.1740+27T>C		intron	N/A	NP_001287714.2	E9PBP6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTTP	ENST00000265517.10	TSL:1 MANE Select	c.1989+27T>C		intron	N/A	ENSP00000265517.5	P55157-1
	MTTP	ENST00000457717.6	TSL:5	c.1989+27T>C		intron	N/A	ENSP00000400821.1	P55157-1
	MTTP	ENST00000511045.6	TSL:2	c.1740+27T>C		intron	N/A	ENSP00000427679.2	E9PBP6

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15852 AN: 152072 Hom.: 994 Cov.: 32

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

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.: 33 AF XY: 0.112 AC XY: 81298 AN XY: 726504

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: 13 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

GnomAD4 genome AF: 0.104 AC: 15872 AN: 152190 Hom.: 995 Cov.: 32 AF XY: 0.103 AC XY: 7631 AN XY: 74410

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: 3 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: 59 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8212 AN: 68008

Other (OTH) AF: 0.120 AC: 253 AN: 2108

Alfa AF: 0.125 Hom.: 2540

Bravo AF: 0.108

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.0
DANN	Benign	0.59
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs745075; hg19: chr4-100532637;