chr8-16164076-G-C

Variant names:

• chr8-16164076-G-C
• rs13306543
• NM_138715.3:c.806C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138715.3(MSR1):​c.806C>G​(p.Thr269Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,254 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSR1 NM_138715.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.90
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.806C>G	p.Thr269Ser	missense	Exon 5 of 10	NP_619729.1	P21757-1
	MSR1	NM_001363744.1		c.860C>G	p.Thr287Ser	missense	Exon 5 of 10	NP_001350673.1	B4DDJ5
	MSR1	NM_138716.3		c.806C>G	p.Thr269Ser	missense	Exon 5 of 9	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.806C>G	p.Thr269Ser	missense	Exon 5 of 10	ENSP00000262101.5	P21757-1
	MSR1	ENST00000445506.6	TSL:1	c.860C>G	p.Thr287Ser	missense	Exon 5 of 10	ENSP00000405453.2	B4DDJ5
	MSR1	ENST00000355282.6	TSL:1	c.806C>G	p.Thr269Ser	missense	Exon 4 of 8	ENSP00000347430.2	P21757-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455254 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723600

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

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 85574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107560

Other (OTH) AF: 0.0000333 AC: 2 AN: 60114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000579 AC: 2 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.35		Gain of glycosylation at T287 (P = 0.0859)
MVP		0.93
MPC		0.0059
ClinPred		0.87	D
GERP RS		3.9
PromoterAI		-0.0062	Neutral
Varity_R		0.096
gMVP		0.24
Mutation Taster		=91/9	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: rs13306543; hg19: chr8-16021585;