chr19-9854485-C-T

Variant names:

• chr19-9854485-C-T
• NM_058164.4:c.1066G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_058164.4(OLFM2):​c.1066G>A​(p.Glu356Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E356G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OLFM2 NM_058164.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OLFM2	NM_058164.4	c.1066G>A	p.Glu356Lys	missense_variant	Exon 6 of 6	ENST00000264833.9	NP_477512.1
OLFM2	NM_001304347.2	c.1138G>A	p.Glu380Lys	missense_variant	Exon 6 of 6		NP_001291276.1
OLFM2	NM_001304348.2	c.832G>A	p.Glu278Lys	missense_variant	Exon 5 of 5		NP_001291277.1
OLFM2	XM_047439713.1	c.862G>A	p.Glu288Lys	missense_variant	Exon 6 of 6		XP_047295669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OLFM2	ENST00000264833.9	c.1066G>A	p.Glu356Lys	missense_variant	Exon 6 of 6	1	NM_058164.4	ENSP00000264833.3
OLFM2	ENST00000593091.2	c.1138G>A	p.Glu380Lys	missense_variant	Exon 6 of 6	5		ENSP00000465809.2
OLFM2	ENST00000590841.5	c.832G>A	p.Glu278Lys	missense_variant	Exon 5 of 5	2		ENSP00000464877.1
OLFM2	ENST00000592448.1	n.*471G>A		downstream_gene_variant		3		ENSP00000466018.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461700 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1066G>A (p.E356K) alteration is located in exon 6 (coding exon 6) of the OLFM2 gene. This alteration results from a G to A substitution at nucleotide position 1066, causing the glutamic acid (E) at amino acid position 356 to be replaced by a lysine (K). 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	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.098	D
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.091	T;T
Polyphen		0.95	P;.
Vest4		0.49
MutPred		0.64		Gain of MoRF binding (P = 0.0106);.;
MVP		0.30
MPC		1.5
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.38

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: chr19-9965161; COSMIC: COSV53432361; COSMIC: COSV53432361;