8-16110218-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_138715.3(MSR1):c.1223G>C(p.Gly408Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSR1 NM_138715.3 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.95

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 8-16110218-C-G is Pathogenic according to our data. Variant chr8-16110218-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2445377.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3	c.1223G>C	p.Gly408Ala	missense_variant, splice_region_variant	10/10	ENST00000262101.10
MSR1	NM_001363744.1	c.1277G>C	p.Gly426Ala	missense_variant, splice_region_variant	10/10
MSR1	NM_138716.3	c.1034G>C	p.Ser345Thr	missense_variant, splice_region_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10	c.1223G>C	p.Gly408Ala	missense_variant, splice_region_variant	10/10	1	NM_138715.3	P1
MSR1	ENST00000445506.6	c.1277G>C	p.Gly426Ala	missense_variant, splice_region_variant	10/10	1
MSR1	ENST00000355282.6	c.1034G>C	p.Ser345Thr	missense_variant, splice_region_variant	8/8	1
MSR1	ENST00000350896.3	c.1034G>C	p.Ser345Thr	missense_variant, splice_region_variant	9/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	29
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.014	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.41
MutPred		0.85		.;Loss of loop (P = 0.1242);
MVP		0.50
MPC		0.014
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-15967727;