Genetic Variant MBLAC2:p.Val140Ile (chr5-90473875-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_203406.2(MBLAC2):c.418G>A(p.Val140Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000562 in 1,601,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MBLAC2
NM_203406.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.87

Variant links:

Genes affected

MBLAC2 (HGNC:33711): (metallo-beta-lactamase domain containing 2) Enables palmitoyl-CoA hydrolase activity. Located in endoplasmic reticulum membrane and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MBLAC2 links:

POLR3G (HGNC:30075): (RNA polymerase III subunit G) Enables chromatin binding activity. Involved in positive regulation of innate immune response; positive regulation of interferon-beta production; and transcription by RNA polymerase III. Acts upstream of or within cell population proliferation. Located in cytosol and nuclear body. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

POLR3G links:

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ACMG classification

Classification made for transcript

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=0.14001492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBLAC2	NM_203406.2 link	c.418G>A	p.Val140Ile	missense_variant	Exon 1 of 2	ENST00000316610.7	NP_981951.2	Q68D91-1B3KY36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MBLAC2	ENST00000316610.7 link	c.418G>A	p.Val140Ile	missense_variant	Exon 1 of 2	1	NM_203406.2	ENSP00000314776.6	Q68D91-1
MBLAC2	ENST00000514906.1 link	c.418G>A	p.Val140Ile	missense_variant	Exon 1 of 1	6		ENSP00000425600.1	Q68D91-2
POLR3G	ENST00000512239.1 link	c.-44+1949C>T		intron_variant	Intron 1 of 1	5		ENSP00000424970.1	D6REQ0
POLR3G	ENST00000505345.5 link	c.-487C>T		upstream_gene_variant		3		ENSP00000427412.1	D6RIT0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000452

AC:

AN:

221182

Hom.:

AF XY:

0.00000829

AC XY:

AN XY:

120556

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1449180

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719638

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418G>A (p.V140I) alteration is located in exon 1 (coding exon 1) of the MBLAC2 gene. This alteration results from a G to A substitution at nucleotide position 418, causing the valine (V) at amino acid position 140 to be replaced by an isoleucine (I). 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

0.15

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.0

L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.11

Sift

Benign

0.32

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0070

B;.

Vest4

0.57

MutPred

0.42

Loss of MoRF binding (P = 0.1225);Loss of MoRF binding (P = 0.1225);

MVP

0.25

MPC

0.29

ClinPred

0.37

GERP RS

4.8

Varity_R

0.31

gMVP

0.46

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

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