chr4-99574925-G-T

Position:

• chr4-99574925-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001386140.1(MTTP):​c.16G>T​(p.Val6Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V6V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTTP NM_001386140.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2384265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTTP	NM_001386140.1	c.16G>T	p.Val6Leu	missense_variant	1/18	ENST00000265517.10
MTTP	NM_000253.4	c.16G>T	p.Val6Leu	missense_variant	2/19
MTTP	NM_001300785.2	c.-188-6980G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTTP	ENST00000265517.10	c.16G>T	p.Val6Leu	missense_variant	1/18	1	NM_001386140.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.16G>T (p.V6L) alteration is located in exon 2 (coding exon 1) of the MTTP gene. This alteration results from a G to T substitution at nucleotide position 16, causing the valine (V) at amino acid position 6 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.31	T;T;D
Polyphen		0.60	P;P;.
Vest4		0.37
MutPred		0.29		Loss of catalytic residue at V6 (P = 0.0444);Loss of catalytic residue at V6 (P = 0.0444);Loss of catalytic residue at V6 (P = 0.0444);
MVP		0.60
MPC		0.24
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100496082;