8-16120615-TTAAAAAAA-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_138715.3(MSR1):c.1034-17_1034-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,288,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSR1 NM_138715.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.86

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 8-16120615-TTAAAAAAA-T is Benign according to our data. Variant chr8-16120615-TTAAAAAAA-T is described in ClinVar as [Benign]. Clinvar id is 3042130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 304 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3	c.1034-17_1034-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262101.10
MSR1	NM_001363744.1	c.1088-17_1088-10del		splice_polypyrimidine_tract_variant, intron_variant
MSR1	NM_138716.3	c.1034-10405_1034-10398del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10	c.1034-17_1034-10del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_138715.3	P1
MSR1	ENST00000355282.6	c.1034-10405_1034-10398del		intron_variant		1
MSR1	ENST00000445506.6	c.1088-17_1088-10del		splice_polypyrimidine_tract_variant, intron_variant		1
MSR1	ENST00000350896.3	c.1034-10405_1034-10398del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 43306 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00664 AC: 304 AN: 45782 Hom.: 0 AF XY: 0.00561 AC XY: 155 AN XY: 27614

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.000279

Gnomad EAS exome AF: 0.0260

Gnomad SAS exome AF: 0.00549

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.000757 AC: 976 AN: 1288754 Hom.: 0 AF XY: 0.000797 AC XY: 506 AN XY: 634720

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00710

Gnomad4 ASJ exome AF: 0.0000911

Gnomad4 EAS exome AF: 0.00461

Gnomad4 SAS exome AF: 0.00251

Gnomad4 FIN exome AF: 0.000264

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 43306 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 20254

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MSR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs751806093; hg19: chr8-15978124;