rs1057147

Variant names:

• chr16-768802-G-A
• rs1057147
• NM_005823.6:c.*69G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005823.6(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 NM_005823.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
MSLN	NM_005823.6	c.*69G>A		3_prime_UTR_variant	Exon 18 of 18	ENST00000545450.7	NP_005814.2
MSLN	NM_013404.4	c.*69G>A		3_prime_UTR_variant	Exon 17 of 17		NP_037536.2
MSLN	NM_001177355.3	c.*69G>A		3_prime_UTR_variant	Exon 18 of 18		NP_001170826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSLN	ENST00000545450.7	c.*69G>A		3_prime_UTR_variant	Exon 18 of 18	1	NM_005823.6	ENSP00000442965.2

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

GnomAD2 exomes AF: 0.210 AC: 47489 AN: 226626 AF XY: 0.206

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 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

African (AFR) AF: 0.231 AC: 7095 AN: 30766

American (AMR) AF: 0.249 AC: 10713 AN: 43046

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 3863 AN: 24926

East Asian (EAS) AF: 0.263 AC: 10172 AN: 38724

South Asian (SAS) AF: 0.191 AC: 15947 AN: 83464

European-Finnish (FIN) AF: 0.171 AC: 7173 AN: 42050

Middle Eastern (MID) AF: 0.187 AC: 1033 AN: 5522

European-Non Finnish (NFE) AF: 0.206 AC: 205949 AN: 1000070

Other (OTH) AF: 0.199 AC: 11118 AN: 55798

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

African (AFR) AF: 0.227 AC: 9419 AN: 41464

American (AMR) AF: 0.210 AC: 3213 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3470

East Asian (EAS) AF: 0.263 AC: 1348 AN: 5124

South Asian (SAS) AF: 0.194 AC: 933 AN: 4820

European-Finnish (FIN) AF: 0.153 AC: 1626 AN: 10622

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14190 AN: 67868

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.207 Hom.: 3311

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25436799) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
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
PhyloP100		0.0
PROVEAN	Benign	0.040	N
Sift	Benign	1.0	T
GERP RS		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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