8-16120616-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant names:

• chr8-16120616-TAA-T
• rs60866666
• NM_138715.3:c.1034-12_1034-11delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_138715.3(MSR1):​c.1034-12_1034-11delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (1126 hom., cov: 0)
  • Exomes 𝑓: 0.26 (412 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSR1 NM_138715.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Barrett esophagus

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138715.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSR1	NM_138715.3	MANE Select	c.1034-12_1034-11delTT		intron	N/A	NP_619729.1	P21757-1
	MSR1	NM_001363744.1		c.1088-12_1088-11delTT		intron	N/A	NP_001350673.1	B4DDJ5
	MSR1	NM_138716.3		c.1034-10400_1034-10399delTT		intron	N/A	NP_619730.1	P21757-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSR1	ENST00000262101.10	TSL:1 MANE Select	c.1034-12_1034-11delTT		intron	N/A	ENSP00000262101.5	P21757-1
	MSR1	ENST00000445506.6	TSL:1	c.1088-12_1088-11delTT		intron	N/A	ENSP00000405453.2	B4DDJ5
	MSR1	ENST00000355282.6	TSL:1	c.1034-10400_1034-10399delTT		intron	N/A	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes AF: 0.233 AC: 14817 AN: 63708 Hom.: 1129 Cov.: 0

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.167

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.217

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.255 AC: 275438 AN: 1078236 Hom.: 412 AF XY: 0.251 AC XY: 133467 AN XY: 532694

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.187 AC: 3939 AN: 21018

American (AMR) AF: 0.148 AC: 3042 AN: 20598

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 3856 AN: 18642

East Asian (EAS) AF: 0.194 AC: 4857 AN: 25024

South Asian (SAS) AF: 0.179 AC: 9973 AN: 55870

European-Finnish (FIN) AF: 0.224 AC: 5557 AN: 24854

Middle Eastern (MID) AF: 0.223 AC: 644 AN: 2892

European-Non Finnish (NFE) AF: 0.269 AC: 232889 AN: 865880

Other (OTH) AF: 0.246 AC: 10681 AN: 43458

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.233 AC: 14816 AN: 63716 Hom.: 1126 Cov.: 0 AF XY: 0.231 AC XY: 6628 AN XY: 28680

African (AFR) AF: 0.270 AC: 4403 AN: 16306

American (AMR) AF: 0.196 AC: 815 AN: 4162

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 394 AN: 2002

East Asian (EAS) AF: 0.148 AC: 309 AN: 2088

South Asian (SAS) AF: 0.181 AC: 268 AN: 1484

European-Finnish (FIN) AF: 0.327 AC: 312 AN: 954

Middle Eastern (MID) AF: 0.167 AC: 10 AN: 60

European-Non Finnish (NFE) AF: 0.226 AC: 8014 AN: 35388

Other (OTH) AF: 0.216 AC: 167 AN: 772

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs60866666; hg19: chr8-15978125;