8-16155139-G-C

Variant names:

• chr8-16155139-G-C
• rs2229388
• NM_138715.3:c.823C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138715.3(MSR1):​c.823C>G​(p.Pro275Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0799 in 1,609,930 control chromosomes in the GnomAD database, including 9,085 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.084 (844 hom., cov: 32)
  • Exomes 𝑓: 0.080 (8241 hom.)
• Consequence: MSR1 NM_138715.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97
• Publications: 54 publications found

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 Gene-Disease associations (from GenCC):

• Barrett esophagus

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002927959).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138715.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSR1	NM_138715.3	MANE Select	c.823C>G	p.Pro275Ala	missense	Exon 6 of 10	NP_619729.1	P21757-1
	MSR1	NM_001363744.1		c.877C>G	p.Pro293Ala	missense	Exon 6 of 10	NP_001350673.1	B4DDJ5
	MSR1	NM_138716.3		c.823C>G	p.Pro275Ala	missense	Exon 6 of 9	NP_619730.1	P21757-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSR1	ENST00000262101.10	TSL:1 MANE Select	c.823C>G	p.Pro275Ala	missense	Exon 6 of 10	ENSP00000262101.5	P21757-1
	MSR1	ENST00000445506.6	TSL:1	c.877C>G	p.Pro293Ala	missense	Exon 6 of 10	ENSP00000405453.2	B4DDJ5
	MSR1	ENST00000355282.6	TSL:1	c.823C>G	p.Pro275Ala	missense	Exon 5 of 8	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12734 AN: 151788 Hom.: 847 Cov.: 32

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0554

Gnomad OTH AF: 0.0922

GnomAD2 exomes AF: 0.113 AC: 28231 AN: 249136 AF XY: 0.111

Gnomad AFR exome AF: 0.0742

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.331

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0825

GnomAD4 exome AF: 0.0795 AC: 115935 AN: 1458024 Hom.: 8241 Cov.: 31 AF XY: 0.0817 AC XY: 59287 AN XY: 725414

African (AFR) AF: 0.0726 AC: 2420 AN: 33352

American (AMR) AF: 0.223 AC: 9910 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.0489 AC: 1273 AN: 26028

East Asian (EAS) AF: 0.375 AC: 14875 AN: 39616

South Asian (SAS) AF: 0.179 AC: 15403 AN: 86086

European-Finnish (FIN) AF: 0.0221 AC: 1176 AN: 53282

Middle Eastern (MID) AF: 0.0714 AC: 411 AN: 5754

European-Non Finnish (NFE) AF: 0.0588 AC: 65266 AN: 1109230

Other (OTH) AF: 0.0864 AC: 5201 AN: 60168

GnomAD4 genome AF: 0.0838 AC: 12737 AN: 151906 Hom.: 844 Cov.: 32 AF XY: 0.0887 AC XY: 6585 AN XY: 74222

African (AFR) AF: 0.0765 AC: 3172 AN: 41488

American (AMR) AF: 0.153 AC: 2321 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 183 AN: 3464

East Asian (EAS) AF: 0.338 AC: 1741 AN: 5146

South Asian (SAS) AF: 0.203 AC: 975 AN: 4804

European-Finnish (FIN) AF: 0.0224 AC: 238 AN: 10606

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0554 AC: 3760 AN: 67892

Other (OTH) AF: 0.0913 AC: 192 AN: 2104

Alfa AF: 0.0610 Hom.: 381

Bravo AF: 0.0941

TwinsUK AF: 0.0558 AC: 207

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0869 AC: 383

ESP6500EA AF: 0.0609 AC: 524

ExAC AF: 0.108 AC: 13155

Asia WGS AF: 0.224 AC: 777 AN: 3478

EpiCase AF: 0.0581

EpiControl AF: 0.0603

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.6	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.0
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MPC		0.015
ClinPred		0.017	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.29
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2229388; hg19: chr8-16012648; COSMIC: COSV50507395;