chr8-16110129-C-G

Position:

• chr8-16110129-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138715.3(MSR1):​c.1312G>C​(p.Ala438Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSR1 NM_138715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.418

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1755206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3	c.1312G>C	p.Ala438Pro	missense_variant	10/10	ENST00000262101.10
MSR1	NM_001363744.1	c.1366G>C	p.Ala456Pro	missense_variant	10/10
MSR1	NM_138716.3	c.1123G>C	p.Ala375Pro	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10	c.1312G>C	p.Ala438Pro	missense_variant	10/10	1	NM_138715.3	P1
MSR1	ENST00000445506.6	c.1366G>C	p.Ala456Pro	missense_variant	10/10	1
MSR1	ENST00000355282.6	c.1123G>C	p.Ala375Pro	missense_variant	8/8	1
MSR1	ENST00000350896.3	c.1123G>C	p.Ala375Pro	missense_variant	9/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.1312G>C (p.A438P) alteration is located in exon 10 (coding exon 9) of the MSR1 gene. This alteration results from a G to C substitution at nucleotide position 1312, causing the alanine (A) at amino acid position 438 to be replaced by a proline (P). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.8
DANN	Benign	0.69
DEOGEN2	Benign	0.024	.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Uncertain	0.93	D;D;D;.
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.52	N;N;N;N
REVEL	Benign	0.022
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.32	B;B;P;B
Vest4		0.18
MutPred		0.63		.;.;Gain of disorder (P = 0.0612);.;
MVP		0.16
MPC		0.0047
ClinPred		0.32	T
GERP RS		-2.5
Varity_R		0.12
gMVP		0.33

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

Other links and lift over

dbSNP: rs1169072459; hg19: chr8-15967638;