8-16120616-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAA

Variant names:

• chr8-16120616-TAAAAA-T
• rs60866666
• NM_138715.3:c.1034-15_1034-11delTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_138715.3(MSR1):​c.1034-15_1034-11delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,181,650 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: MSR1 NM_138715.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the MID (0.0186) population. However there is too low homozygotes in high coverage region: (expected more than 55, got 0).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000157 (10/63504) while in subpopulation EAS AF = 0.00144 (3/2082). AF 95% confidence interval is 0.000392. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.1034-15_1034-11delTTTTT		intron	N/A	NP_619729.1	P21757-1
	MSR1	NM_001363744.1		c.1088-15_1088-11delTTTTT		intron	N/A	NP_001350673.1	B4DDJ5
	MSR1	NM_138716.3		c.1034-10403_1034-10399delTTTTT		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.1034-15_1034-11delTTTTT		intron	N/A	ENSP00000262101.5	P21757-1
	MSR1	ENST00000445506.6	TSL:1	c.1088-15_1088-11delTTTTT		intron	N/A	ENSP00000405453.2	B4DDJ5
	MSR1	ENST00000355282.6	TSL:1	c.1034-10403_1034-10399delTTTTT		intron	N/A	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes AF: 0.000157 AC: 10 AN: 63502 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00144

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000285

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0145 AC: 16202 AN: 1118146 Hom.: 0 AF XY: 0.0144 AC XY: 7966 AN XY: 553038

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

African (AFR) AF: 0.0164 AC: 364 AN: 22136

American (AMR) AF: 0.0119 AC: 262 AN: 21972

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 392 AN: 19156

East Asian (EAS) AF: 0.0130 AC: 357 AN: 27404

South Asian (SAS) AF: 0.00698 AC: 417 AN: 59736

European-Finnish (FIN) AF: 0.0225 AC: 578 AN: 25682

Middle Eastern (MID) AF: 0.0230 AC: 69 AN: 3004

European-Non Finnish (NFE) AF: 0.0146 AC: 13006 AN: 893768

Other (OTH) AF: 0.0167 AC: 757 AN: 45288

⚠️ 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: 0.000157 AC: 10 AN: 63504 Hom.: 0 Cov.: 0 AF XY: 0.000175 AC XY: 5 AN XY: 28560

African (AFR) AF: 0.000121 AC: 2 AN: 16470

American (AMR) AF: 0.00 AC: 0 AN: 4160

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 3 AN: 1986

East Asian (EAS) AF: 0.00144 AC: 3 AN: 2082

South Asian (SAS) AF: 0.00 AC: 0 AN: 1490

European-Finnish (FIN) AF: 0.00107 AC: 1 AN: 938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 58

European-Non Finnish (NFE) AF: 0.0000285 AC: 1 AN: 35062

Other (OTH) AF: 0.00 AC: 0 AN: 766

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs60866666; hg19: chr8-15978125;