rs1888156

chr9-126340561-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_033446.3(MVB12B):c.135G>A(p.Thr45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,613,512 control chromosomes in the GnomAD database, including 83,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (8357 hom., cov: 33)
  • Exomes 𝑓: 0.32 (75576 hom.)
• Consequence: MVB12B NM_033446.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.969

Genes affected

MVB12B (HGNC:23368): (multivesicular body subunit 12B) The protein encoded by this gene is a component of the ESCRT-I complex, a heterotetramer, which mediates the sorting of ubiquitinated cargo protein from the plasma membrane to the endosomal vesicle. ESCRT-I complex plays an essential role in HIV budding and endosomal protein sorting. Depletion and overexpression of this and related protein (MVB12A) inhibit HIV-1 infectivity and induce unusual viral assembly defects, indicating a role for MVB12 subunits in regulating ESCRT-mediated virus budding. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 9-126340561-G-A is Benign according to our data. Variant chr9-126340561-G-A is described in ClinVar as [Benign]. Clinvar id is 3060638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.969 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVB12B	NM_033446.3	c.135G>A	p.Thr45=	synonymous_variant	2/10	ENST00000361171.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVB12B	ENST00000361171.8	c.135G>A	p.Thr45=	synonymous_variant	2/10	2	NM_033446.3	P1
MVB12B	ENST00000489637.3	c.135G>A	p.Thr45=	synonymous_variant	2/6	1
MVB12B	ENST00000402437.2	c.90G>A	p.Thr30=	synonymous_variant	2/6	3

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50094 AN: 151984 Hom.: 8353 Cov.: 33

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.323 AC: 81233 AN: 251450 Hom.: 13482 AF XY: 0.319 AC XY: 43345 AN XY: 135898

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.294

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.319 AC: 466914 AN: 1461410 Hom.: 75576 Cov.: 34 AF XY: 0.318 AC XY: 231052 AN XY: 727012

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.320

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.329 AC: 50116 AN: 152102 Hom.: 8357 Cov.: 33 AF XY: 0.331 AC XY: 24614 AN XY: 74332

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.307

Alfa AF: 0.313 Hom.: 12839

Bravo AF: 0.326

Asia WGS AF: 0.302 AC: 1050 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.297

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MVB12B-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	6.1
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1888156; hg19: chr9-129102840; COSMIC: COSV63257354;