Genetic Variant ORM1:p.Lys170Arg (chr9-114325121-A-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_000607.4(ORM1):c.509A>G(p.Lys170Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,612,954 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 9 hom. )

Consequence

ORM1
NM_000607.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.337

Publications

5 publications found

Variant links:

Genes affected

ORM1 (HGNC:8498): (orosomucoid 1) This gene encodes a key acute phase plasma protein. Because of its increase due to acute inflammation, this protein is classified as an acute-phase reactant. The specific function of this protein has not yet been determined; however, it may be involved in aspects of immunosuppression. [provided by RefSeq, Jul 2008]

ORM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORM1	NM_000607.4 link	c.509A>G	p.Lys170Arg	missense_variant	Exon 5 of 6	ENST00000259396.9	NP_000598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORM1	ENST00000259396.9 link	c.509A>G	p.Lys170Arg	missense_variant	Exon 5 of 6	1	NM_000607.4	ENSP00000259396.8
ORM1	ENST00000477456.1 link	n.292A>G		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00340

AC:

517

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0187

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00737

AC:

1848

AN:

250898

AF XY:

0.00609

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0303

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.0162

Gnomad FIN exome

AF:

0.00804

Gnomad NFE exome

AF:

0.000820

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00269

AC:

3934

AN:

1460912

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

1878

AN XY:

726798

show subpopulations

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

African (AFR)

AF:

0.000299

AC:

AN:

33446

American (AMR)

AF:

0.0284

AC:

1266

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26132

East Asian (EAS)

AF:

0.0210

AC:

830

AN:

39592

South Asian (SAS)

AF:

0.00649

AC:

559

AN:

86180

European-Finnish (FIN)

AF:

0.00886

AC:

473

AN:

53380

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000528

AC:

587

AN:

1111524

Other (OTH)

AF:

0.00312

AC:

188

AN:

60340

⚠️ 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: 0.352

Heterozygous variant carriers

223

446

669

892

1115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00342

AC:

520

AN:

152042

Hom.:

Cov.:

AF XY:

0.00441

AC XY:

328

AN XY:

74330

show subpopulations

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

African (AFR)

AF:

0.000725

AC:

AN:

41374

American (AMR)

AF:

0.0129

AC:

197

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0188

AC:

AN:

5168

South Asian (SAS)

AF:

0.00767

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0105

AC:

111

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68026

Other (OTH)

AF:

0.00474

AC:

AN:

2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.351

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000852

Hom.:

ExAC

AF:

0.00678

AC:

823

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.45

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.038

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.94

PhyloP100

0.34

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

REVEL

Benign

0.015

Sift

Benign

0.48

Sift4G

Benign

0.33

Vest4

0.15

ClinPred

0.0034

GERP RS

-1.9

gMVP

0.14

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.57

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.57

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over