9-114330016-C-G

Variant names:

• chr9-114330016-C-G
• rs370008862
• NM_000608.4:c.112C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000608.4(ORM2):​c.112C>G​(p.Arg38Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 145,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R38W) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000069 (0 hom., cov: 20)
• Consequence: ORM2 NM_000608.4 missense, splice_region
• Scores: Splicing: ADA: 0.0008802
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070298225).

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.112C>G	p.Arg38Gly	missense splice_region	Exon 1 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.112C>G	p.Arg38Gly	missense splice_region	Exon 1 of 6	ENSP00000394936.2	P19652
	ORM2	ENST00000893195.1		c.112C>G	p.Arg38Gly	missense splice_region	Exon 1 of 7	ENSP00000563254.1
	ORM2	ENST00000893198.1		c.112C>G	p.Arg38Gly	missense splice_region	Exon 1 of 6	ENSP00000563257.1

Frequencies

GnomAD3 genomes AF: 0.00000686 AC: 1 AN: 145756 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000686 AC: 1 AN: 145756 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 71012

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

African (AFR) AF: 0.00 AC: 0 AN: 36736

American (AMR) AF: 0.00 AC: 0 AN: 14860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5034

South Asian (SAS) AF: 0.00 AC: 0 AN: 4612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67442

Other (OTH) AF: 0.00 AC: 0 AN: 2012

⚠️ 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.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.0
DANN	Benign	0.67
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		-1.1
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.037
Sift	Benign	0.11	T
Sift4G	Benign	0.34	T
Polyphen		0.46	P
Vest4		0.21
MutPred		0.32		Loss of MoRF binding (P = 0.0771)
MVP		0.16
MPC		2.1
ClinPred		0.19	T
GERP RS		-5.3
PromoterAI		-0.047	Neutral
Varity_R		0.23
gMVP		0.42
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.11
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: rs370008862; hg19: chr9-117092296;