16-764946-C-G

Position:

• chr16-764946-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005823.6(MSLN):​c.420C>G​(p.Phe140Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSLN NM_005823.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.290

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSLN	NM_005823.6	c.420C>G	p.Phe140Leu	missense_variant	8/18	ENST00000545450.7	NP_005814.2
MSLN	NM_013404.4	c.420C>G	p.Phe140Leu	missense_variant	7/17		NP_037536.2
MSLN	NM_001177355.3	c.420C>G	p.Phe140Leu	missense_variant	8/18		NP_001170826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSLN	ENST00000545450.7	c.420C>G	p.Phe140Leu	missense_variant	8/18	1	NM_005823.6	ENSP00000442965	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.420C>G (p.F140L) alteration is located in exon 7 (coding exon 6) of the MSLN gene. This alteration results from a C to G substitution at nucleotide position 420, causing the phenylalanine (F) at amino acid position 140 to be replaced by a leucine (L). 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	Pathogenic	0.86
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.25	.;.;.;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.39	.;.;T;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.047	D;D;D;D;T;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;.;.
Vest4		0.53
MutPred		0.79		Gain of MoRF binding (P = 0.1286);Gain of MoRF binding (P = 0.1286);Gain of MoRF binding (P = 0.1286);Gain of MoRF binding (P = 0.1286);Gain of MoRF binding (P = 0.1286);Gain of MoRF binding (P = 0.1286);
MVP		0.18
MPC		0.081
ClinPred		0.87	D
GERP RS		0.26
Varity_R		0.23
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-814946;