8-16120489-C-A

Variant names:

• chr8-16120489-C-A
• rs762767495
• NM_138715.3:c.1151G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138715.3(MSR1):​c.1151G>T​(p.Gly384Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MSR1 NM_138715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.766
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

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.1151G>T	p.Gly384Val	missense	Exon 9 of 10	NP_619729.1	P21757-1
	MSR1	NM_001363744.1		c.1205G>T	p.Gly402Val	missense	Exon 9 of 10	NP_001350673.1	B4DDJ5
	MSR1	NM_138716.3		c.1034-10271G>T		intron	N/A	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.1151G>T	p.Gly384Val	missense	Exon 9 of 10	ENSP00000262101.5	P21757-1
	MSR1	ENST00000445506.6	TSL:1	c.1205G>T	p.Gly402Val	missense	Exon 9 of 10	ENSP00000405453.2	B4DDJ5
	MSR1	ENST00000355282.6	TSL:1	c.1034-10271G>T		intron	N/A	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251456 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.091	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.77
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.69		Gain of MoRF binding (P = 0.1268)
MVP		0.52
MPC		0.012
ClinPred		0.93	D
GERP RS		1.9
Varity_R		0.53
gMVP		0.66
Mutation Taster		=73/27	polymorphism

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: rs762767495; hg19: chr8-15977998;