Genetic Variant NM_138401.4:c.88G>A (chr19-17420223-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_138401.4(MVB12A):c.88G>A(p.Ala30Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A30P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

MVB12A
NM_138401.4 missense, splice_region

Scores

Splicing: ADA: 0.6237

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.99

Publications

0 publications found

Variant links:

Genes affected

MVB12A (HGNC:25153): (multivesicular body subunit 12A) Enables lipid binding activity and ubiquitin binding activity. Involved in regulation of epidermal growth factor receptor signaling pathway; viral budding; and virus maturation. Located in several cellular components, including Golgi apparatus; centrosome; and nucleoplasm. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

MVB12A links:

ENSG00000269481 (HGNC:):

ENSG00000269481 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28520727).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138401.4. 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
	MVB12A	NM_138401.4	MANE Select	c.88G>A	p.Ala30Thr	missense splice_region	Exon 1 of 9	NP_612410.1	Q96EY5-1
	MVB12A	NM_001304547.2		c.-186-90G>A		intron	N/A	NP_001291476.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MVB12A	ENST00000317040.12	TSL:1 MANE Select	c.88G>A	p.Ala30Thr	missense splice_region	Exon 1 of 9	ENSP00000324810.6	Q96EY5-1
MVB12A	ENST00000529939.5	TSL:3	c.88G>A	p.Ala30Thr	missense splice_region	Exon 1 of 8	ENSP00000432526.1	E9PQA6
MVB12A	ENST00000875213.1		c.88G>A	p.Ala30Thr	missense splice_region	Exon 1 of 8	ENSP00000545272.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000760

AC:

AN:

131580

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000155

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.47e-7

AC:

AN:

1338514

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

655490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28724

American (AMR)

AF:

0.00

AC:

AN:

25344

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19792

East Asian (EAS)

AF:

0.00

AC:

AN:

35940

South Asian (SAS)

AF:

0.00

AC:

AN:

67302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5026

European-Non Finnish (NFE)

AF:

9.45e-7

AC:

AN:

1058572

Other (OTH)

AF:

0.00

AC:

AN:

55156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000856

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0087

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.81

M_CAP

Benign

0.028

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.7

PhyloP100

2.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.76

REVEL

Benign

0.16

Sift

Benign

0.062

Sift4G

Benign

0.085

Polyphen

0.99

Vest4

0.38

MVP

0.68

MPC

0.45

ClinPred

0.73

GERP RS

4.9

PromoterAI

0.072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.16

gMVP

0.18

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.62

dbscSNV1_RF

Benign

0.59

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over