Variant chr19-9856809-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_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

Variant links:

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]

OLFM2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, OLFM2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460256

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726376

show subpopulations

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.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.1

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over