16-768802-G-A

Position:

• chr16-768802-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000545450.7(MSLN):​c.*69G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,476,340 control chromosomes in the GnomAD database, including 31,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3415 hom., cov: 32)
  • Exomes 𝑓: 0.21 (28566 hom.)
• Consequence: MSLN ENST00000545450.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043660104).
• BP6: Variant 16-768802-G-A is Benign according to our data. Variant chr16-768802-G-A is described in ClinVar as [Benign]. Clinvar id is 1232817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSLN	NM_005823.6	c.*69G>A		3_prime_UTR_variant	18/18	ENST00000545450.7	NP_005814.2
MSLN	NM_001177355.3	c.*69G>A		3_prime_UTR_variant	18/18		NP_001170826.1
MSLN	NM_013404.4	c.*69G>A		3_prime_UTR_variant	17/17		NP_037536.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSLN	ENST00000545450.7	c.*69G>A		3_prime_UTR_variant	18/18	1	NM_005823.6	ENSP00000442965	P2

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31905 AN: 151856 Hom.: 3414 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.210 AC: 47489 AN: 226626 Hom.: 4911 AF XY: 0.206 AC XY: 25669 AN XY: 124682

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.237

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.206 AC: 273063 AN: 1324366 Hom.: 28566 Cov.: 20 AF XY: 0.206 AC XY: 136767 AN XY: 664832

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.263

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.210 AC: 31919 AN: 151974 Hom.: 3415 Cov.: 32 AF XY: 0.207 AC XY: 15344 AN XY: 74300

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.181

Alfa AF: 0.208 Hom.: 1994

Bravo AF: 0.215

TwinsUK AF: 0.210 AC: 779

ALSPAC AF: 0.205 AC: 791

ExAC AF: 0.203 AC: 24257

Asia WGS AF: 0.237 AC: 826 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 25436799) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.9
DANN	Benign	0.66
DEOGEN2	Benign	0.0078	T
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0044	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PROVEAN	Benign	0.040	N
Sift	Benign	1.0	T
GERP RS		-2.7

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: rs1057147; hg19: chr16-818802; COSMIC: COSV53499533; COSMIC: COSV53499533;