NM_000608.4:c.490G>A

Variant names:

• chr9-114331879-G-A
• rs148221879
• NM_000608.4:c.490G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000608.4(ORM2):​c.490G>A​(p.Asp164Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000628 in 1,613,836 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D164H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (10 hom.)
• Consequence: ORM2 NM_000608.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 0 publications found

Genes affected

ORM2 (HGNC:8499): (orosomucoid 2) 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]

AKNA (HGNC:24108): (AT-hook transcription factor) Predicted to enable DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in centrosome; cytosol; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.005784869).
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000608.4. 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
	ORM2	NM_000608.4	MANE Select	c.490G>A	p.Asp164Asn	missense	Exon 5 of 6	NP_000599.1	P19652

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORM2	ENST00000431067.4	TSL:1 MANE Select	c.490G>A	p.Asp164Asn	missense	Exon 5 of 6	ENSP00000394936.2	P19652
	ORM2	ENST00000893195.1		c.490G>A	p.Asp164Asn	missense	Exon 5 of 7	ENSP00000563254.1
	ORM2	ENST00000893198.1		c.514G>A	p.Asp172Asn	missense	Exon 5 of 6	ENSP00000563257.1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152080 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000729 AC: 183 AN: 251138 AF XY: 0.000435

Gnomad AFR exome AF: 0.00991

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000387 AC: 565 AN: 1461638 Hom.: 10 Cov.: 31 AF XY: 0.000351 AC XY: 255 AN XY: 727126

African (AFR) AF: 0.0116 AC: 389 AN: 33458

American (AMR) AF: 0.000268 AC: 12 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1111834

Other (OTH) AF: 0.000696 AC: 42 AN: 60376

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152198 Hom.: 7 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74420

African (AFR) AF: 0.0103 AC: 425 AN: 41454

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00329

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000889 AC: 108

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.4
PROVEAN	Benign	0.13	N
REVEL	Benign	0.051
Sift	Benign	0.20	T
Sift4G	Benign	0.48	T
Polyphen		0.69	P
Vest4		0.16
MVP		0.15
MPC		0.028
ClinPred		0.018	T
GERP RS		-5.1
Varity_R		0.15
gMVP		0.18
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148221879; hg19: chr9-117094159;