8-16155085-G-A

Position:

chr8-16155085-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_138715.3(MSR1):c.877C>T(p.Arg293Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00983 in 1,611,828 control chromosomes in the GnomAD database, including 150 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0084 ( 13 hom., cov: 32)

Exomes 𝑓: 0.010 ( 137 hom. )

Consequence

MSR1
NM_138715.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:4

Conservation

PhyloP100: 1.22

Variant links:

Genes affected

MSR1 (HGNC:7376): (macrophage scavenger receptor 1) This gene encodes the class A macrophage scavenger receptors, which include three different types (1, 2, 3) generated by alternative splicing of this gene. These receptors or isoforms are macrophage-specific trimeric integral membrane glycoproteins and have been implicated in many macrophage-associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense. The isoforms type 1 and type 2 are functional receptors and are able to mediate the endocytosis of modified low density lipoproteins (LDLs). The isoform type 3 does not internalize modified LDL (acetyl-LDL) despite having the domain shown to mediate this function in the types 1 and 2 isoforms. It has an altered intracellular processing and is trapped within the endoplasmic reticulum, making it unable to perform endocytosis. The isoform type 3 can inhibit the function of isoforms type 1 and type 2 when co-expressed, indicating a dominant negative effect and suggesting a mechanism for regulation of scavenger receptor activity in macrophages. [provided by RefSeq, Jul 2008]

MSR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High AC in GnomAd4 at 1282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSR1	NM_138715.3 linkuse as main transcript	c.877C>T	p.Arg293Ter	stop_gained	6/10	ENST00000262101.10	NP_619729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSR1	ENST00000262101.10 linkuse as main transcript	c.877C>T	p.Arg293Ter	stop_gained	6/10	1	NM_138715.3	ENSP00000262101	P1	P21757-1

Frequencies

GnomAD3 genomes

AF:

0.00845

AC:

1283

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0130

GnomAD3 exomes

AF:

0.00829

AC:

2078

AN:

250570

Hom.:

AF XY:

0.00831

AC XY:

1126

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00926

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.00997

AC:

14556

AN:

1459882

Hom.:

137

Cov.:

AF XY:

0.00984

AC XY:

7144

AN XY:

726302

show subpopulations

Gnomad4 AFR exome

AF:

0.00177

Gnomad4 AMR exome

AF:

0.0117

Gnomad4 ASJ exome

AF:

0.0140

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000870

Gnomad4 FIN exome

AF:

0.00935

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00844

AC:

1282

AN:

151946

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

622

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.0131

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00835

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00977

AC:

ExAC

AF:

0.00735

AC:

892

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.00979

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2017	The R293X variant in the MSR1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been reported previously in several individuals with a diagnosis of Barrett's esophagus and/or esophageal adenocarcinoma (Orloff et al., 2011); however, specific phenotypic details and familial segregation information were not provided. The R293X variant has also been reported previously in association with prostate cancer in multiple individuals with and without a family history of prostate cancer, although segregation of R293X with cancer was incomplete in several families (Xu et al., 2002; Gonzalez-Garay et al., 2013). In addition, a study assessing the frequency of MSR1 variants in individuals with prostate cancer identified R293X in equal frequency among both familial and sporadic prostate cancer cohorts as well as an equal frequency among healthy controls (Maier et al., 2006). The R293X variant is observed in 890/119706 (0.01%%) alleles in the ExAC dataset, including 13 homozygotes (Lek et al., 2016). We interpret R293X as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MSR1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSR1 p.R293* variant was identified in 45 of 4502 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer and 10 of 348 proband chromosomes (frequency: 0.029) from individuals with Barrett esophagus and esophageal adenocarcinoma, but was also identified in 26 of 2636 control chromosomes (frequency: 0.0099) from healthy individuals (Orloff_2011_PMID:21791690; Xu_2002_PMID:12244320; Wang_2003_PMID:12958598; Maier_2006_PMID:16287155; Seppala_2003_PMID:14614006). An association study of almost 3,000 prostate cancer cases and 2,800 controls did not identify a significant difference in the frequency of R293* in cases compared to controls (Hope_2005_PMID:15734964). The variant was identified in dbSNP (ID: rs41341748), ClinVar (classified as a VUS by GeneDx and as pathogenic by Vantari Genetics) and Cosmic (FATHMM prediction of neutral; score=0.08). The variant was also identified in control databases in 2324 of 281916 chromosomes (23 homozygous) at a frequency of 0.008244 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 155 of 10344 chromosomes (freq: 0.01498), Latino in 413 of 35264 chromosomes (freq: 0.01171), Other in 82 of 7174 chromosomes (freq: 0.01143), European (non-Finnish) in 1370 of 128636 chromosomes (freq: 0.01065), European (Finnish) in 231 of 25070 chromosomes (freq: 0.009214), African in 50 of 24926 chromosomes (freq: 0.002006), South Asian in 22 of 30596 chromosomes (freq: 0.000719), and East Asian in 1 of 19906 chromosomes (freq: 0.00005). The c.877C>T variant leads to a premature stop codon at position 293 which is predicted to lead to a truncated or absent protein and loss of function. The role of loss of function variants of the MSR1 gene in disease is currently unclear. Western blots of the MSR1 protein in patients with Barrett esophagus and esophageal adenocarcinoma carrying the R293* variant showed MSR1 protein expression, although at lower level in some patients (Orloff_2011_PMID:21791690). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Malignant tumor of prostate

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 27, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, flagged submission

clinical testing

Vantari Genetics

Dec 07, 2015

- -

Barrett esophagus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 23, 2019

- -

MSR1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

X-linked Alport syndrome

Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg293Ter variant in MSR1 has been identified in 8 individuals with prostate cancer and multiple individuals without reported prostate cancer (PMID: 12244320, 21791690, 24082139, 25333069), but has also been identified in >1% of Latino chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg293Ter variant may slightly impact protein function (PMID: 21791690). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant prostate cancer. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Benign

-0.032

FATHMM_MKL

Benign

0.076

MutationTaster

Benign

1.0

A;A;A;A;A;A

Vest4

0.73

GERP RS

2.8

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