19-9854527-C-T

Variant names:

• chr19-9854527-C-T
• rs767544450
• NM_058164.4:c.1024G>A

Variant summary

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

The NM_058164.4(OLFM2):​c.1024G>A​(p.Ala342Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OLFM2 NM_058164.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81

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.1024G>A	p.Ala342Thr	missense_variant	Exon 6 of 6	ENST00000264833.9	NP_477512.1
OLFM2	NM_001304347.2	c.1096G>A	p.Ala366Thr	missense_variant	Exon 6 of 6		NP_001291276.1
OLFM2	NM_001304348.2	c.790G>A	p.Ala264Thr	missense_variant	Exon 5 of 5		NP_001291277.1
OLFM2	XM_047439713.1	c.820G>A	p.Ala274Thr	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.1024G>A	p.Ala342Thr	missense_variant	Exon 6 of 6	1	NM_058164.4	ENSP00000264833.3
OLFM2	ENST00000593091.2	c.1096G>A	p.Ala366Thr	missense_variant	Exon 6 of 6	5		ENSP00000465809.2
OLFM2	ENST00000590841.5	c.790G>A	p.Ala264Thr	missense_variant	Exon 5 of 5	2		ENSP00000464877.1
OLFM2	ENST00000592448.1	n.*429G>A		downstream_gene_variant		3		ENSP00000466018.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251130 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461578 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Sep 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1024G>A (p.A342T) 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 1024, causing the alanine (A) at amino acid position 342 to be replaced by a threonine (T). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.99	N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.016	D;.
Sift4G	Uncertain	0.047	D;T
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.40		Loss of sheet (P = 0.302);.;
MVP		0.35
MPC		1.7
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.12

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: rs767544450; hg19: chr19-9965203; COSMIC: COSV53431181; COSMIC: COSV53431181;