rs72552387

chr8-16168568-C-Achr8-16168568-C-Gchr8-16168568-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_138715.3(MSR1):c.520G>T(p.Asp174Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,614,122 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (16 hom.)
• Consequence: MSR1 NM_138715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.11

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07389018).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00623 (949/152300) while in subpopulation AFR AF= 0.0216 (896/41566). AF 95% confidence interval is 0.0204. There are 10 homozygotes in gnomad4. There are 467 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 948 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3	c.520G>T	p.Asp174Tyr	missense_variant	4/10	ENST00000262101.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10	c.520G>T	p.Asp174Tyr	missense_variant	4/10	1	NM_138715.3	P1

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 948 AN: 152182 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00165 AC: 414 AN: 251352 Hom.: 4 AF XY: 0.00132 AC XY: 179 AN XY: 135844

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000692 AC: 1011 AN: 1461822 Hom.: 16 Cov.: 32 AF XY: 0.000638 AC XY: 464 AN XY: 727202

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00623 AC: 949 AN: 152300 Hom.: 10 Cov.: 33 AF XY: 0.00627 AC XY: 467 AN XY: 74450

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000880 Hom.: 1

Bravo AF: 0.00673

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Malignant tumor of prostate Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	19
Dann	Uncertain	0.98
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.89	D;D;D;.;D
MetaRNN	Benign	0.074	T;T;T;T;T
MetaSVM	Uncertain	0.0096	D
MutationAssessor	Uncertain	2.3	M;M;.;M;M
MutationTaster	Benign	6.5e-8	A;A;A;A;A;A
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.68
MVP		0.87
MPC		0.010
ClinPred		0.028	T
GERP RS		3.4
Varity_R		0.16
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72552387; hg19: chr8-16026077; COSMIC: COSV50508400; COSMIC: COSV50508400;