9-135120012-A-G

Position:

• chr9-135120012-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001282611.2(OLFM1):​c.1292A>G​(p.Asn431Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OLFM1 NM_001282611.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.05

Genes affected

OLFM1 (HGNC:17187): (olfactomedin 1) This gene product shares extensive sequence similarity with the rat neuronal olfactomedin-related ER localized protein. While the exact function of the encoded protein is not known, its abundant expression in brain suggests that it may have an essential role in nerve tissue. Several alternatively spliced transcripts encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity NOE1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OLFM1	NM_001282611.2	c.1292A>G	p.Asn431Ser	missense_variant	6/6	ENST00000371793.8	NP_001269540.1
OLFM1	NM_014279.5	c.1238A>G	p.Asn413Ser	missense_variant	6/6		NP_055094.1
OLFM1	NM_001282612.1	c.1211A>G	p.Asn404Ser	missense_variant	6/6		NP_001269541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OLFM1	ENST00000371793.8	c.1292A>G	p.Asn431Ser	missense_variant	6/6	3	NM_001282611.2	ENSP00000360858	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jul 25, 2023

The c.1238A>G (p.N413S) alteration is located in exon 6 (coding exon 6) of the OLFM1 gene. This alteration results from a A to G substitution at nucleotide position 1238, causing the asparagine (N) at amino acid position 413 to be replaced by a serine (S). 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	0.083
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.6	.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.085	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.74
MutPred		0.34		.;.;Gain of glycosylation at N431 (P = 0.0222);
MVP		0.63
MPC		1.9
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.17
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-138011858;