chr8-16120616-TAAA-T

Variant names:

• chr8-16120616-TAAA-T
• rs60866666
• NM_138715.3:c.1034-13_1034-11delTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_138715.3(MSR1):​c.1034-13_1034-11delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,148,482 control chromosomes in the GnomAD database, including 20 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (5 hom., cov: 0)
  • Exomes 𝑓: 0.12 (15 hom.)
• Consequence: MSR1 NM_138715.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (640/63504) while in subpopulation AFR AF = 0.027 (445/16462). AF 95% confidence interval is 0.025. There are 5 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 Unknown gene

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.1034-13_1034-11delTTT		intron	N/A	NP_619729.1	P21757-1
	MSR1	NM_001363744.1		c.1088-13_1088-11delTTT		intron	N/A	NP_001350673.1	B4DDJ5
	MSR1	NM_138716.3		c.1034-10401_1034-10399delTTT		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.1034-13_1034-11delTTT		intron	N/A	ENSP00000262101.5	P21757-1
	MSR1	ENST00000445506.6	TSL:1	c.1088-13_1088-11delTTT		intron	N/A	ENSP00000405453.2	B4DDJ5
	MSR1	ENST00000355282.6	TSL:1	c.1034-10401_1034-10399delTTT		intron	N/A	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 638 AN: 63502 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00817

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.000959

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00656

GnomAD4 exome AF: 0.122 AC: 132510 AN: 1084978 Hom.: 15 AF XY: 0.121 AC XY: 64981 AN XY: 535740

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

African (AFR) AF: 0.0973 AC: 2099 AN: 21568

American (AMR) AF: 0.0862 AC: 1815 AN: 21062

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2203 AN: 18752

East Asian (EAS) AF: 0.0975 AC: 2545 AN: 26112

South Asian (SAS) AF: 0.0865 AC: 4885 AN: 56494

European-Finnish (FIN) AF: 0.141 AC: 3545 AN: 25096

Middle Eastern (MID) AF: 0.111 AC: 320 AN: 2890

European-Non Finnish (NFE) AF: 0.126 AC: 109793 AN: 869106

Other (OTH) AF: 0.121 AC: 5305 AN: 43898

⚠️ 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: 0.0101 AC: 640 AN: 63504 Hom.: 5 Cov.: 0 AF XY: 0.0103 AC XY: 295 AN XY: 28552

African (AFR) AF: 0.0270 AC: 445 AN: 16462

American (AMR) AF: 0.00817 AC: 34 AN: 4160

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 36 AN: 1988

East Asian (EAS) AF: 0.000961 AC: 2 AN: 2082

South Asian (SAS) AF: 0.0155 AC: 23 AN: 1486

European-Finnish (FIN) AF: 0.00320 AC: 3 AN: 938

Middle Eastern (MID) AF: 0.0172 AC: 1 AN: 58

European-Non Finnish (NFE) AF: 0.00259 AC: 91 AN: 35072

Other (OTH) AF: 0.00653 AC: 5 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		1.5
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;