Genetic Variant NM_138715.3:c.1034-14_1034-11dupTTTT (chr8-16120616-T-TAAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_138715.3(MSR1):c.1034-14_1034-11dupTTTT 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 0.029 ( 45 hom., cov: 0)

Exomes 𝑓: 0.011 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

MSR1
NM_138715.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.140

Publications

0 publications found

Variant links:

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

MSR1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_138715.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSR1	NM_138715.3	MANE Select	c.1034-14_1034-11dupTTTT	intron	N/A	NP_619729.1	P21757-1
MSR1	NM_001363744.1		c.1088-14_1088-11dupTTTT	intron	N/A	NP_001350673.1	B4DDJ5
MSR1	NM_138716.3		c.1034-10402_1034-10399dupTTTT	intron	N/A	NP_619730.1	P21757-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSR1	ENST00000262101.10	TSL:1 MANE Select	c.1034-11_1034-10insTTTT	intron	N/A	ENSP00000262101.5	P21757-1
MSR1	ENST00000445506.6	TSL:1	c.1088-11_1088-10insTTTT	intron	N/A	ENSP00000405453.2	B4DDJ5
MSR1	ENST00000355282.6	TSL:1	c.1034-10399_1034-10398insTTTT	intron	N/A	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes

AF:

0.0293

AC:

1856

AN:

63410

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0386

Gnomad AMI

AF:

0.00610

Gnomad AMR

AF:

0.0488

Gnomad ASJ

AF:

0.0272

Gnomad EAS

AF:

0.0953

Gnomad SAS

AF:

0.0160

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.0172

Gnomad NFE

AF:

0.0198

Gnomad OTH

AF:

0.0406

GnomAD4 exome

AF:

0.0108

AC:

12082

AN:

1120268

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

5880

AN XY:

554792

show subpopulations

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

African (AFR)

AF:

0.0169

AC:

372

AN:

22026

American (AMR)

AF:

0.0202

AC:

445

AN:

22048

Ashkenazi Jewish (ASJ)

AF:

0.00990

AC:

192

AN:

19400

East Asian (EAS)

AF:

0.0210

AC:

572

AN:

27266

South Asian (SAS)

AF:

0.00445

AC:

268

AN:

60210

European-Finnish (FIN)

AF:

0.00942

AC:

246

AN:

26120

Middle Eastern (MID)

AF:

0.00628

AC:

AN:

3024

European-Non Finnish (NFE)

AF:

0.0105

AC:

9435

AN:

894716

Other (OTH)

AF:

0.0117

AC:

533

AN:

45458

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

Heterozygous variant carriers

754

1508

2262

3016

3770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

404

808

1212

1616

2020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0293

AC:

1855

AN:

63410

Hom.:

Cov.:

AF XY:

0.0304

AC XY:

866

AN XY:

28498

show subpopulations

African (AFR)

AF:

0.0386

AC:

635

AN:

16452

American (AMR)

AF:

0.0488

AC:

202

AN:

4138

Ashkenazi Jewish (ASJ)

AF:

0.0272

AC:

AN:

1986

East Asian (EAS)

AF:

0.0954

AC:

197

AN:

2064

South Asian (SAS)

AF:

0.0162

AC:

AN:

1484

European-Finnish (FIN)

AF:

0.0150

AC:

AN:

936

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0198

AC:

694

AN:

35032

Other (OTH)

AF:

0.0404

AC:

AN:

768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.553

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over