Genetic Variant MSR1:c.1034-13_1034-11dupTTT (chr8-16120616-T-TAAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_138715.3(MSR1):c.1034-13_1034-11dupTTT 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 0.0042 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0080 ( 6 hom. )

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

ACMG classification

Classification was made for transcript

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

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00417 (265/63482) while in subpopulation AFR AF = 0.0145 (238/16448). AF 95% confidence interval is 0.013. There are 3 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.1034-13_1034-11dupTTT	intron	N/A	NP_619729.1	P21757-1
MSR1	NM_001363744.1		c.1088-13_1088-11dupTTT	intron	N/A	NP_001350673.1	B4DDJ5
MSR1	NM_138716.3		c.1034-10401_1034-10399dupTTT	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_1034-10insTTT	intron	N/A	ENSP00000262101.5	P21757-1
MSR1	ENST00000445506.6	TSL:1	c.1088-11_1088-10insTTT	intron	N/A	ENSP00000405453.2	B4DDJ5
MSR1	ENST00000355282.6	TSL:1	c.1034-10399_1034-10398insTTT	intron	N/A	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

264

AN:

63480

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000504

Gnomad EAS

AF:

0.00240

Gnomad SAS

AF:

0.000664

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000285

Gnomad OTH

AF:

0.00131

GnomAD4 exome

AF:

0.00798

AC:

8954

AN:

1122508

Hom.:

Cov.:

AF XY:

0.00793

AC XY:

4406

AN XY:

555870

show subpopulations

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

African (AFR)

AF:

0.0206

AC:

453

AN:

21954

American (AMR)

AF:

0.0208

AC:

458

AN:

22024

Ashkenazi Jewish (ASJ)

AF:

0.00747

AC:

145

AN:

19422

East Asian (EAS)

AF:

0.0217

AC:

592

AN:

27220

South Asian (SAS)

AF:

0.00482

AC:

290

AN:

60168

European-Finnish (FIN)

AF:

0.00874

AC:

228

AN:

26078

Middle Eastern (MID)

AF:

0.00856

AC:

AN:

3036

European-Non Finnish (NFE)

AF:

0.00708

AC:

6349

AN:

897120

Other (OTH)

AF:

0.00908

AC:

413

AN:

45486

⚠️ 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: 0.323

Heterozygous variant carriers

549

1098

1647

2196

2745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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

AF:

0.00417

AC:

265

AN:

63482

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

128

AN XY:

28554

show subpopulations

African (AFR)

AF:

0.0145

AC:

238

AN:

16448

American (AMR)

AF:

0.00216

AC:

AN:

4160

Ashkenazi Jewish (ASJ)

AF:

0.000504

AC:

AN:

1986

East Asian (EAS)

AF:

0.00240

AC:

AN:

2082

South Asian (SAS)

AF:

0.000671

AC:

AN:

1490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

938

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000285

AC:

AN:

35062

Other (OTH)

AF:

0.00131

AC:

AN:

766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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

Publications

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8-16120616-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAA

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