Variant chr16-763660-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005823.6(MSLN):c.148G>A(p.Gly50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,586,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

MSLN
NM_005823.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0800

Variant links:

Genes affected

MSLN (HGNC:7371): (mesothelin) This gene encodes a preproprotein that is proteolytically processed to generate two protein products, megakaryocyte potentiating factor and mesothelin. Megakaryocyte potentiating factor functions as a cytokine that can stimulate colony formation of bone marrow megakaryocytes. Mesothelin is a glycosylphosphatidylinositol-anchored cell-surface protein that may function as a cell adhesion protein. This protein is overexpressed in epithelial mesotheliomas, ovarian cancers and in specific squamous cell carcinomas. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

MSLN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34415954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSLN	NM_005823.6 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	5/18	ENST00000545450.7	NP_005814.2	Q13421-3
MSLN	NM_013404.4 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	4/17		NP_037536.2	Q13421-1
MSLN	NM_001177355.3 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	5/18		NP_001170826.1	Q13421-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSLN	ENST00000545450.7 linkuse as main transcript	c.148G>A	p.Gly50Arg	missense_variant	5/18	1	NM_005823.6	ENSP00000442965.2		Q13421-3

Frequencies

GnomAD3 genomes

AF:

0.00000706

AC:

AN:

141708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000301

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

GnomAD4 exome

AF:

0.00000415

AC:

AN:

1444866

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000363

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000706

AC:

AN:

141708

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68682

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000301

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:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2024

The c.148G>A (p.G50R) alteration is located in exon 4 (coding exon 3) of the MSLN gene. This alteration results from a G to A substitution at nucleotide position 148, causing the glycine (G) at amino acid position 50 to be replaced by an arginine (R). 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

0.098

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.050

.;.;.;T;T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.43

.;.;T;T;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.34

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L;L;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.35

N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.35

T;T;T;T;T;T

Sift4G

Benign

0.068

T;T;T;T;T;T

Polyphen

0.94

P;P;P;P;.;.

Vest4

0.070

MutPred

0.75

Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);

MVP

0.35

MPC

0.051

ClinPred

0.38

GERP RS

0.55

Varity_R

0.062

gMVP

0.30

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