19-9854277-C-T

Variant names:

• chr19-9854277-C-T
• rs750019375
• NM_058164.4:c.1274G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_058164.4(OLFM2):​c.1274G>A​(p.Arg425Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: OLFM2 NM_058164.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

Genes affected

OLFM2 (HGNC:17189): (olfactomedin 2) Involved in positive regulation of smooth muscle cell differentiation. Acts upstream of or within protein secretion. Located in cytoplasm; extracellular region; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OLFM2	NM_058164.4	c.1274G>A	p.Arg425Gln	missense_variant	Exon 6 of 6	ENST00000264833.9	NP_477512.1
OLFM2	NM_001304347.2	c.1346G>A	p.Arg449Gln	missense_variant	Exon 6 of 6		NP_001291276.1
OLFM2	NM_001304348.2	c.1040G>A	p.Arg347Gln	missense_variant	Exon 5 of 5		NP_001291277.1
OLFM2	XM_047439713.1	c.1070G>A	p.Arg357Gln	missense_variant	Exon 6 of 6		XP_047295669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OLFM2	ENST00000264833.9	c.1274G>A	p.Arg425Gln	missense_variant	Exon 6 of 6	1	NM_058164.4	ENSP00000264833.3
OLFM2	ENST00000593091.2	c.1346G>A	p.Arg449Gln	missense_variant	Exon 6 of 6	5		ENSP00000465809.2
OLFM2	ENST00000590841.5	c.1040G>A	p.Arg347Gln	missense_variant	Exon 5 of 5	2		ENSP00000464877.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251482 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1274G>A (p.R425Q) alteration is located in exon 6 (coding exon 6) of the OLFM2 gene. This alteration results from a G to A substitution at nucleotide position 1274, causing the arginine (R) at amino acid position 425 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.1	N;.
REVEL	Pathogenic	0.70
Sift	Benign	0.15	T;.
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.39
MutPred		0.71		Gain of catalytic residue at R425 (P = 0.0165);.;
MVP		0.53
MPC		1.8
ClinPred		0.92	D
GERP RS		4.3
Varity_R		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs750019375; hg19: chr19-9964953;