8-16120512-G-A

Position:

• chr8-16120512-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138715.3(MSR1):​c.1128C>T​(p.Asp376=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,084 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (80 hom., cov: 29)
  • Exomes 𝑓: 0.0019 (61 hom.)
• Consequence: MSR1 NM_138715.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.927

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-16120512-G-A is Benign according to our data. Variant chr8-16120512-G-A is described in ClinVar as [Benign]. Clinvar id is 782031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.927 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3	c.1128C>T	p.Asp376=	synonymous_variant	9/10	ENST00000262101.10
MSR1	NM_001363744.1	c.1182C>T	p.Asp394=	synonymous_variant	9/10
MSR1	NM_138716.3	c.1034-10294C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10	c.1128C>T	p.Asp376=	synonymous_variant	9/10	1	NM_138715.3	P1
MSR1	ENST00000445506.6	c.1182C>T	p.Asp394=	synonymous_variant	9/10	1
MSR1	ENST00000355282.6	c.1034-10294C>T		intron_variant		1
MSR1	ENST00000350896.3	c.1034-10294C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2557 AN: 151148 Hom.: 80 Cov.: 29

Gnomad AFR AF: 0.0579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00456 AC: 1147 AN: 251446 Hom.: 30 AF XY: 0.00325 AC XY: 442 AN XY: 135894

Gnomad AFR exome AF: 0.0597

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00192 AC: 2800 AN: 1461824 Hom.: 61 Cov.: 31 AF XY: 0.00169 AC XY: 1229 AN XY: 727204

Gnomad4 AFR exome AF: 0.0620

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.0170 AC: 2565 AN: 151260 Hom.: 80 Cov.: 29 AF XY: 0.0166 AC XY: 1225 AN XY: 73834

Gnomad4 AFR AF: 0.0580

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.00861 Hom.: 14

Bravo AF: 0.0197

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.33
DANN	Benign	0.72

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: rs35962364; hg19: chr8-15978021; COSMIC: COSV50508381; COSMIC: COSV50508381;