1-161984867-C-A

Variant names:

• chr1-161984867-C-A
• rs749921063
• NM_015441.3:c.1588G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015441.3(OLFML2B):​c.1588G>T​(p.Val530Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OLFML2B NM_015441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OLFML2B	NM_015441.3	c.1588G>T	p.Val530Leu	missense_variant	Exon 7 of 8	ENST00000294794.8	NP_056256.1
OLFML2B	NM_001347700.2	c.1594G>T	p.Val532Leu	missense_variant	Exon 7 of 8		NP_001334629.1
OLFML2B	NM_001297713.2	c.1591G>T	p.Val531Leu	missense_variant	Exon 7 of 8		NP_001284642.1
OLFML2B	XM_011509398.3	c.868G>T	p.Val290Leu	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.1588G>T	p.Val530Leu	missense_variant	Exon 7 of 8	1	NM_015441.3	ENSP00000294794.3
OLFML2B	ENST00000367940.2	c.1591G>T	p.Val531Leu	missense_variant	Exon 7 of 8	2		ENSP00000356917.2
OLFML2B	ENST00000367938.1	c.37G>T	p.Val13Leu	missense_variant	Exon 1 of 2	2		ENSP00000356915.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1588G>T (p.V530L) alteration is located in exon 7 (coding exon 7) of the OLFML2B gene. This alteration results from a G to T substitution at nucleotide position 1588, causing the valine (V) at amino acid position 530 to be replaced by a leucine (L). 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	0.77
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Pathogenic	0.80
Sift	Benign	0.059	T;T;T
Sift4G	Uncertain	0.0090	D;D;T
Polyphen		0.75	P;P;.
Vest4		0.82
MutPred		0.61		.;Gain of catalytic residue at V531 (P = 0.0722);.;
MVP		0.89
MPC		0.45
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.26
gMVP		0.72

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: rs749921063; hg19: chr1-161954657;