8-16120602-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138715.3(MSR1):c.1038A>G(p.Pro346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,549,842 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (17 hom., cov: 21)
  • Exomes 𝑓: 0.0032 (139 hom.)
• Consequence: MSR1 NM_138715.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.989

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-16120602-T-C is Benign according to our data. Variant chr8-16120602-T-C is described in ClinVar as [Benign]. Clinvar id is 778941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.989 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3	c.1038A>G	p.Pro346=	synonymous_variant	9/10	ENST00000262101.10
MSR1	NM_001363744.1	c.1092A>G	p.Pro364=	synonymous_variant	9/10
MSR1	NM_138716.3	c.1034-10384A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10	c.1038A>G	p.Pro346=	synonymous_variant	9/10	1	NM_138715.3	P1
MSR1	ENST00000445506.6	c.1092A>G	p.Pro364=	synonymous_variant	9/10	1
MSR1	ENST00000355282.6	c.1034-10384A>G		intron_variant		1
MSR1	ENST00000350896.3	c.1034-10384A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 589 AN: 99100 Hom.: 17 Cov.: 21

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0852

Gnomad SAS AF: 0.00217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000166

Gnomad OTH AF: 0.0114

GnomAD3 exomes AF: 0.0103 AC: 2335 AN: 226504 Hom.: 73 AF XY: 0.00873 AC XY: 1078 AN XY: 123522

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.0333

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0749

Gnomad SAS exome AF: 0.00187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000579

Gnomad OTH exome AF: 0.00597

GnomAD4 exome AF: 0.00316 AC: 4589 AN: 1450726 Hom.: 139 Cov.: 38 AF XY: 0.00292 AC XY: 2105 AN XY: 721670

Gnomad4 AFR exome AF: 0.000642

Gnomad4 AMR exome AF: 0.0288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0695

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000929

Gnomad4 OTH exome AF: 0.00546

GnomAD4 genome AF: 0.00594 AC: 589 AN: 99116 Hom.: 17 Cov.: 21 AF XY: 0.00670 AC XY: 300 AN XY: 44752

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0852

Gnomad4 SAS AF: 0.00218

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000166

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00334 Hom.: 5

Asia WGS AF: 0.0340 AC: 116 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MSR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.36
Dann	Benign	0.45

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: rs34175190; hg19: chr8-15978111; COSMIC: COSV50538691; COSMIC: COSV50538691;