4-99581979-C-G

Variant names:

• chr4-99581979-C-G
• rs141736123
• NM_001386140.1:c.136C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001300785.2(MTTP):​c.-114C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,614,112 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (322 hom.)
• Consequence: MTTP NM_001300785.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.29
• Publications: 14 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=0.00479275).
• BP6: Variant 4-99581979-C-G is Benign according to our data. Variant chr4-99581979-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 347020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0138 (2097/152274) while in subpopulation SAS AF = 0.0349 (168/4818). AF 95% confidence interval is 0.0306. There are 22 homozygotes in GnomAd4. There are 1088 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300785.2. 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.136C>G	p.Arg46Gly	missense	Exon 2 of 18	NP_001373069.1	P55157-1
	MTTP	NM_001300785.2		c.-114C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001287714.2	E9PBP6
	MTTP	NM_000253.4		c.136C>G	p.Arg46Gly	missense	Exon 3 of 19	NP_000244.2	P55157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTTP	ENST00000265517.10	TSL:1 MANE Select	c.136C>G	p.Arg46Gly	missense	Exon 2 of 18	ENSP00000265517.5	P55157-1
	MTTP	ENST00000422897.6	TSL:1	c.136C>G	p.Arg46Gly	missense	Exon 2 of 3	ENSP00000407350.2	P55157-2
	MTTP	ENST00000511045.6	TSL:2	c.-114C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	ENSP00000427679.2	E9PBP6

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2098 AN: 152156 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0187 AC: 4696 AN: 251466 AF XY: 0.0202

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00755

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0347

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0176 AC: 25710 AN: 1461838 Hom.: 322 Cov.: 31 AF XY: 0.0183 AC XY: 13325 AN XY: 727222

African (AFR) AF: 0.00278 AC: 93 AN: 33478

American (AMR) AF: 0.00745 AC: 333 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00647 AC: 169 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0394 AC: 3401 AN: 86256

European-Finnish (FIN) AF: 0.0308 AC: 1643 AN: 53420

Middle Eastern (MID) AF: 0.0359 AC: 207 AN: 5768

European-Non Finnish (NFE) AF: 0.0170 AC: 18920 AN: 1111960

Other (OTH) AF: 0.0156 AC: 941 AN: 60396

GnomAD4 genome AF: 0.0138 AC: 2097 AN: 152274 Hom.: 22 Cov.: 32 AF XY: 0.0146 AC XY: 1088 AN XY: 74448

African (AFR) AF: 0.00253 AC: 105 AN: 41578

American (AMR) AF: 0.0111 AC: 170 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0349 AC: 168 AN: 4818

European-Finnish (FIN) AF: 0.0327 AC: 346 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1239 AN: 68022

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0125 Hom.: 8

Bravo AF: 0.0110

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0176 AC: 151

ExAC AF: 0.0189 AC: 2295

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0190

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Abetalipoproteinaemia (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.089
Sift	Benign	0.31	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.083
MPC		0.30
ClinPred		0.0077	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.42
Mutation Taster		=81/19	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: rs141736123; hg19: chr4-100503136; COSMIC: COSV106094527; COSMIC: COSV106094527;