8-16110212-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_138715.3(MSR1):​c.1229G>T​(p.Gly410Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,180 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: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSR1
NM_138715.3 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSR1NM_138715.3 linkc.1229G>T p.Gly410Val missense_variant Exon 10 of 10 ENST00000262101.10 NP_619729.1 P21757-1
MSR1NM_001363744.1 linkc.1283G>T p.Gly428Val missense_variant Exon 10 of 10 NP_001350673.1
MSR1NM_138716.3 linkc.1040G>T p.Gly347Val missense_variant Exon 9 of 9 NP_619730.1 P21757-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSR1ENST00000262101.10 linkc.1229G>T p.Gly410Val missense_variant Exon 10 of 10 1 NM_138715.3 ENSP00000262101.5 P21757-1
MSR1ENST00000445506.6 linkc.1283G>T p.Gly428Val missense_variant Exon 10 of 10 1 ENSP00000405453.2 B4DDJ5
MSR1ENST00000355282.6 linkc.1040G>T p.Gly347Val missense_variant Exon 8 of 8 1 ENSP00000347430.2 P21757-3
MSR1ENST00000350896.3 linkc.1040G>T p.Gly347Val missense_variant Exon 9 of 9 5 ENSP00000262100.3 P21757-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461180
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726892
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 29, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1229G>T (p.G410V) alteration is located in exon 10 (coding exon 9) of the MSR1 gene. This alteration results from a G to T substitution at nucleotide position 1229, causing the glycine (G) at amino acid position 410 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
.;T;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.93
D;D;D;.
M_CAP
Benign
0.066
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Benign
-0.30
T
MutationAssessor
Pathogenic
3.4
.;M;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-5.6
D;D;D;D
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0090
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.67
MutPred
0.88
.;.;Loss of loop (P = 0.1242);.;
MVP
0.65
MPC
0.013
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.96
gMVP
0.62

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.

Other links and lift over

dbSNP: rs575983341; hg19: chr8-15967721; API