9-114323246-G-C

Variant names:

• chr9-114323246-G-C
• rs17650
• NM_000607.4:c.113G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000607.4(ORM1):​c.113G>C​(p.Arg38Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. R38Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ORM1 NM_000607.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004954
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28648293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORM1	NM_000607.4	c.113G>C	p.Arg38Pro	missense_variant, splice_region_variant	Exon 1 of 6	ENST00000259396.9	NP_000598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORM1	ENST00000259396.9	c.113G>C	p.Arg38Pro	missense_variant, splice_region_variant	Exon 1 of 6	1	NM_000607.4	ENSP00000259396.8

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000141 AC: 2 AN: 1421726 Hom.: 0 Cov.: 34 AF XY: 0.00000283 AC XY: 2 AN XY: 705940

African (AFR) AF: 0.00 AC: 0 AN: 31752

American (AMR) AF: 0.00 AC: 0 AN: 40454

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 37474

South Asian (SAS) AF: 0.00 AC: 0 AN: 82578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088408

Other (OTH) AF: 0.00 AC: 0 AN: 58586

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.6
DANN	Benign	0.62
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.4
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.032
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Vest4		0.43
MutPred		0.41		Gain of glycosylation at T35 (P = 0.0426);
MVP		0.12
MPC		3.3
ClinPred		0.24	T
GERP RS		-7.6
PromoterAI		0.020	Neutral
gMVP		0.85
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.022
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: rs17650; hg19: chr9-117085526;