NM_138715.3:c.1173G>C

Variant names:

• chr8-16120467-C-G
• rs1163411232
• NM_138715.3:c.1173G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138715.3(MSR1):​c.1173G>C​(p.Leu391Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,842 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: 0.0000014 (0 hom.)
• Consequence: MSR1 NM_138715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

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.1173G>C	p.Leu391Phe	missense	Exon 9 of 10	NP_619729.1	P21757-1
	MSR1	NM_001363744.1		c.1227G>C	p.Leu409Phe	missense	Exon 9 of 10	NP_001350673.1	B4DDJ5
	MSR1	NM_138716.3		c.1034-10249G>C		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.1173G>C	p.Leu391Phe	missense	Exon 9 of 10	ENSP00000262101.5	P21757-1
	MSR1	ENST00000445506.6	TSL:1	c.1227G>C	p.Leu409Phe	missense	Exon 9 of 10	ENSP00000405453.2	B4DDJ5
	MSR1	ENST00000355282.6	TSL:1	c.1034-10249G>C		intron	N/A	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251466 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

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: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.67
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	4.8	H
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.90		Loss of MoRF binding (P = 0.1465)
MVP		0.58
MPC		0.013
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.52
gMVP		0.29
Mutation Taster		=71/29	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: rs1163411232; hg19: chr8-15977976;