rs3816873

Variant names:

• chr4-99583507-T-C
• rs3816873
• NM_001386140.1:c.383T>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.383T>C​(p.Ile128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,613,128 control chromosomes in the GnomAD database, including 55,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5382 hom., cov: 32)
  • Exomes 𝑓: 0.26 (49652 hom.)
• Consequence: MTTP NM_001386140.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.741
• Publications: 81 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.649328E-4).
• BP6: Variant 4-99583507-T-C is Benign according to our data. Variant chr4-99583507-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 14242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 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.383T>C	p.Ile128Thr	missense	Exon 3 of 18	NP_001373069.1	P55157-1
	MTTP	NM_000253.4		c.383T>C	p.Ile128Thr	missense	Exon 4 of 19	NP_000244.2	P55157-1
	MTTP	NM_001300785.2		c.134T>C	p.Ile45Thr	missense	Exon 3 of 18	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.383T>C	p.Ile128Thr	missense	Exon 3 of 18	ENSP00000265517.5	P55157-1
	MTTP	ENST00000422897.6	TSL:1	c.383T>C	p.Ile128Thr	missense	Exon 3 of 3	ENSP00000407350.2	P55157-2
	MTTP	ENST00000457717.6	TSL:5	c.383T>C	p.Ile128Thr	missense	Exon 4 of 19	ENSP00000400821.1	P55157-1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39787 AN: 151904 Hom.: 5374 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.297

GnomAD2 exomes AF: 0.248 AC: 61707 AN: 248600 AF XY: 0.255

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.257 AC: 374829 AN: 1461106 Hom.: 49652 Cov.: 35 AF XY: 0.260 AC XY: 189092 AN XY: 726840

African (AFR) AF: 0.282 AC: 9422 AN: 33458

American (AMR) AF: 0.168 AC: 7532 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10399 AN: 26120

East Asian (EAS) AF: 0.152 AC: 6029 AN: 39656

South Asian (SAS) AF: 0.342 AC: 29458 AN: 86228

European-Finnish (FIN) AF: 0.188 AC: 9999 AN: 53152

Middle Eastern (MID) AF: 0.352 AC: 2030 AN: 5764

European-Non Finnish (NFE) AF: 0.255 AC: 283730 AN: 1111638

Other (OTH) AF: 0.269 AC: 16230 AN: 60376

GnomAD4 genome AF: 0.262 AC: 39818 AN: 152022 Hom.: 5382 Cov.: 32 AF XY: 0.261 AC XY: 19359 AN XY: 74306

African (AFR) AF: 0.278 AC: 11525 AN: 41490

American (AMR) AF: 0.237 AC: 3619 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1385 AN: 3472

East Asian (EAS) AF: 0.146 AC: 757 AN: 5178

South Asian (SAS) AF: 0.347 AC: 1672 AN: 4818

European-Finnish (FIN) AF: 0.190 AC: 2007 AN: 10566

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17682 AN: 67922

Other (OTH) AF: 0.298 AC: 627 AN: 2106

Alfa AF: 0.264 Hom.: 21115

Bravo AF: 0.261

TwinsUK AF: 0.254 AC: 940

ALSPAC AF: 0.271 AC: 1043

ESP6500AA AF: 0.272 AC: 1197

ESP6500EA AF: 0.258 AC: 2218

ExAC AF: 0.249 AC: 30226

Asia WGS AF: 0.291 AC: 1008 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.265

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Abetalipoproteinaemia (2)
-	-	1	Abetalipoproteinaemia;C4552048:Metabolic syndrome X (1)
-	-	1	METABOLIC SYNDROME, PROTECTION AGAINST (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.00056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.74
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.070
Sift	Benign	0.64	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.026
MPC		0.30
ClinPred		0.0061	T
GERP RS		4.1
Varity_R		0.074
gMVP		0.24
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3816873; hg19: chr4-100504664; COSMIC: COSV55504606; COSMIC: COSV55504606;