Variant 8-16150297-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_138715.3(MSR1):c.913A>G(p.Lys305Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MSR1
NM_138715.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

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]

MSR1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3 linkuse as main transcript	c.913A>G	p.Lys305Glu	missense_variant	7/10	ENST00000262101.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10 linkuse as main transcript	c.913A>G	p.Lys305Glu	missense_variant	7/10	1	NM_138715.3	P1	P21757-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000829

AC:

AN:

241338

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

130936

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000317

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000906

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1424876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708988

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:

9.17e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.913A>G (p.K305E) alteration is located in exon 7 (coding exon 6) of the MSR1 gene. This alteration results from a A to G substitution at nucleotide position 913, causing the lysine (K) at amino acid position 305 to be replaced by a glutamic acid (E). 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

Benign

0.29

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.80

T;T;T;.;T;T

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.44

T;T;T;T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.1

M;M;.;M;.;M

MutationTaster

Benign

0.57

N;N;N;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.0

N;D;D;N;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0070

D;D;D;D;D;D

Sift4G

Benign

0.12

T;T;T;T;T;T

Polyphen

1.0

D;D;D;D;.;P

Vest4

0.40

MutPred

0.39

.;.;Loss of ubiquitination at K323 (P = 0.0037);.;.;.;

MVP

0.94

MPC

0.012

ClinPred

0.88

GERP RS

3.3

Varity_R

0.33

gMVP

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over