8-16120614-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_138715.3(MSR1):c.1034-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 0)
  • Exomes 𝑓: 0.051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSR1 NM_138715.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001490
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.999

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-16120614-G-T is Benign according to our data. Variant chr8-16120614-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 746739.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSR1	NM_138715.3	c.1034-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262101.10
MSR1	NM_001363744.1	c.1088-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
MSR1	NM_138716.3	c.1034-10396C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSR1	ENST00000262101.10	c.1034-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_138715.3	P1
MSR1	ENST00000355282.6	c.1034-10396C>A		intron_variant		1
MSR1	ENST00000445506.6	c.1088-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
MSR1	ENST00000350896.3	c.1034-10396C>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 34 AN: 42682 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.000859

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.00137

Gnomad FIN AF: 0.00450

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000329

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0514 AC: 31570 AN: 614246 Hom.: 0 Cov.: 26 AF XY: 0.0478 AC XY: 14906 AN XY: 311638

Gnomad4 AFR exome AF: 0.0559

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.0235

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0591

Gnomad4 OTH exome AF: 0.0454

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000820 AC: 35 AN: 42686 Hom.: 0 Cov.: 0 AF XY: 0.000893 AC XY: 18 AN XY: 20148

Gnomad4 AFR AF: 0.00112

Gnomad4 AMR AF: 0.000592

Gnomad4 ASJ AF: 0.000859

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00138

Gnomad4 FIN AF: 0.00450

Gnomad4 NFE AF: 0.000330

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.1
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.022
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: rs550192996; hg19: chr8-15978123;