1-161984849-C-A

Variant names:

• chr1-161984849-C-A
• rs185436876
• NM_015441.3:c.1606G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_015441.3(OLFML2B):​c.1606G>T​(p.Gly536Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G536S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 27)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OLFML2B NM_015441.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-161984849-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 217141.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015441.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OLFML2B	NM_015441.3	MANE Select	c.1606G>T	p.Gly536Cys	missense	Exon 7 of 8	NP_056256.1	Q68BL8-1
	OLFML2B	NM_001347700.2		c.1612G>T	p.Gly538Cys	missense	Exon 7 of 8	NP_001334629.1
	OLFML2B	NM_001297713.2		c.1609G>T	p.Gly537Cys	missense	Exon 7 of 8	NP_001284642.1	F2Z3N3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OLFML2B	ENST00000294794.8	TSL:1 MANE Select	c.1606G>T	p.Gly536Cys	missense	Exon 7 of 8	ENSP00000294794.3	Q68BL8-1
	OLFML2B	ENST00000367940.2	TSL:2	c.1609G>T	p.Gly537Cys	missense	Exon 7 of 8	ENSP00000356917.2	F2Z3N3
	OLFML2B	ENST00000367938.1	TSL:2	c.55G>T	p.Gly19Cys	missense	Exon 1 of 2	ENSP00000356915.1	Q68BL8-2

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150854 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000244

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150854 Hom.: 0 Cov.: 27 AF XY: 0.0000136 AC XY: 1 AN XY: 73528

African (AFR) AF: 0.0000244 AC: 1 AN: 40958

American (AMR) AF: 0.00 AC: 0 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.0000149 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.95
MPC		0.58
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		-0.065	Neutral
Varity_R		0.81
gMVP		0.90
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs185436876; hg19: chr1-161954639;