19-9856809-G-A

Position:

• chr19-9856809-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_058164.4(OLFM2):​c.685C>T​(p.Arg229Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OLFM2 NM_058164.4 missense, splice_region
• Scores: Splicing: ADA: 0.3696
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.674

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OLFM2	NM_058164.4	c.685C>T	p.Arg229Trp	missense_variant, splice_region_variant	5/6	ENST00000264833.9
OLFM2	NM_001304347.2	c.757C>T	p.Arg253Trp	missense_variant, splice_region_variant	5/6
OLFM2	NM_001304348.2	c.451C>T	p.Arg151Trp	missense_variant, splice_region_variant	4/5
OLFM2	XM_047439713.1	c.481C>T	p.Arg161Trp	missense_variant, splice_region_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OLFM2	ENST00000264833.9	c.685C>T	p.Arg229Trp	missense_variant, splice_region_variant	5/6	1	NM_058164.4
OLFM2	ENST00000593091.2	c.757C>T	p.Arg253Trp	missense_variant, splice_region_variant	5/6	5		P1
OLFM2	ENST00000590841.5	c.451C>T	p.Arg151Trp	missense_variant, splice_region_variant	4/5	2
OLFM2	ENST00000592448.1	c.*90C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460256 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

The c.685C>T (p.R229W) alteration is located in exon 5 (coding exon 5) of the OLFM2 gene. This alteration results from a C to T substitution at nucleotide position 685, causing the arginine (R) at amino acid position 229 to be replaced by a tryptophan (W). 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0040	D;.;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.82
MutPred		0.79		Loss of disorder (P = 0.052);.;.;
MVP		0.66
MPC		1.7
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.37
dbscSNV1_RF	Benign	0.42
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: rs1289831457; hg19: chr19-9967485;