Genetic Variant NM_003791.4:c.2963-12G>A (chr16-84054657-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_003791.4(MBTPS1):c.2963-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,570,212 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 1 hom. )

Consequence

MBTPS1
NM_003791.4 intron

Scores

Splicing: ADA: 0.00001267

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.240

Variant links:

Genes affected

MBTPS1 (HGNC:15456): (membrane bound transcription factor peptidase, site 1) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the cis/medial-Golgi where a second autocatalytic event takes place and the catalytic activity is acquired. It encodes a type 1 membrane bound protease which is ubiquitously expressed and regulates cholesterol or lipid homeostasis via cleavage of substrates at non-basic residues. Mutations in this gene may be associated with lysosomal dysfunction. [provided by RefSeq, Feb 2014]

MBTPS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-84054657-C-T is Benign according to our data. Variant chr16-84054657-C-T is described in ClinVar as [Benign]. Clinvar id is 1629994.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0019 (289/152362) while in subpopulation AMR AF= 0.00333 (51/15306). AF 95% confidence interval is 0.0026. There are 0 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MBTPS1	NM_003791.4 link	c.2963-12G>A	intron_variant	Intron 22 of 22	ENST00000343411.8	NP_003782.1	Q14703
MBTPS1	XM_047434830.1 link	c.2963-12G>A	intron_variant	Intron 22 of 22		XP_047290786.1
MBTPS1	XM_047434831.1 link	c.2963-12G>A	intron_variant	Intron 22 of 22		XP_047290787.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MBTPS1	ENST00000343411.8 link	c.2963-12G>A	intron_variant	Intron 22 of 22	1	NM_003791.4	ENSP00000344223.3	Q14703
MBTPS1	ENST00000562886.1 link	n.2462-12G>A	intron_variant	Intron 2 of 2	2
MBTPS1	ENST00000562906.2 link	n.2041-12G>A	intron_variant	Intron 1 of 1	2
MBTPS1	ENST00000570064.5 link	n.2207-12G>A	intron_variant	Intron 11 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.00190

AC:

289

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00613

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00198

AC:

422

AN:

213582

Hom.:

AF XY:

0.00180

AC XY:

209

AN XY:

115978

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000527

Gnomad FIN exome

AF:

0.00578

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00301

GnomAD4 exome

AF:

0.00170

AC:

2414

AN:

1417850

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

1166

AN XY:

701348

show subpopulations

Gnomad4 AFR exome

AF:

0.000188

Gnomad4 AMR exome

AF:

0.00283

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.000590

Gnomad4 FIN exome

AF:

0.00543

Gnomad4 NFE exome

AF:

0.00172

Gnomad4 OTH exome

AF:

0.00151

GnomAD4 genome

AF:

0.00190

AC:

289

AN:

152362

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00613

Gnomad4 NFE

AF:

0.00222

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00161

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.85

CADD

Benign

2.2

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over