chr1-161984875-C-T

Variant names:

• chr1-161984875-C-T
• rs756430892
• NM_015441.3:c.1580G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015441.3(OLFML2B):​c.1580G>A​(p.Arg527Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: OLFML2B NM_015441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.21

Genes affected

OLFML2B (HGNC:24558): (olfactomedin like 2B) This gene encodes an olfactomedin domain-containing protein. Most olfactomedin domain-containing proteins are secreted glycoproteins. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30183753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OLFML2B	NM_015441.3	c.1580G>A	p.Arg527Gln	missense_variant	Exon 7 of 8	ENST00000294794.8	NP_056256.1
OLFML2B	NM_001347700.2	c.1586G>A	p.Arg529Gln	missense_variant	Exon 7 of 8		NP_001334629.1
OLFML2B	NM_001297713.2	c.1583G>A	p.Arg528Gln	missense_variant	Exon 7 of 8		NP_001284642.1
OLFML2B	XM_011509398.3	c.860G>A	p.Arg287Gln	missense_variant	Exon 4 of 5		XP_011507700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OLFML2B	ENST00000294794.8	c.1580G>A	p.Arg527Gln	missense_variant	Exon 7 of 8	1	NM_015441.3	ENSP00000294794.3
OLFML2B	ENST00000367940.2	c.1583G>A	p.Arg528Gln	missense_variant	Exon 7 of 8	2		ENSP00000356917.2
OLFML2B	ENST00000367938.1	c.29G>A	p.Arg10Gln	missense_variant	Exon 1 of 2	2		ENSP00000356915.1

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 AN: 150540 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000147

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: 0.000486

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251462 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135900

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727224

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150540 Hom.: 0 Cov.: 27 AF XY: 0.0000273 AC XY: 2 AN XY: 73300

Gnomad4 AFR AF: 0.000147

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000486

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 01, 2015

Medizinische Klinik 1/ Institut für Bioinformatik, Universitätsklinikum Großhadern, München/ Helmholtz Zentrum München

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1580G>A (p.R527Q) alteration is located in exon 7 (coding exon 7) of the OLFML2B gene. This alteration results from a G to A substitution at nucleotide position 1580, causing the arginine (R) at amino acid position 527 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	0.17
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.59	P;P;.
Vest4		0.52
MutPred		0.43		.;Gain of catalytic residue at R528 (P = 0.0888);.;
MVP		0.84
MPC		0.38
ClinPred		0.26	T
GERP RS		4.3
Varity_R		0.27
gMVP		0.68

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: rs756430892; hg19: chr1-161954665;