rs773856461

Variant names:

• chr19-9854629-C-T
• rs773856461
• NM_058164.4:c.922G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-9854629-C-T
• chr19-9854629-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_058164.4(OLFM2):​c.922G>A​(p.Gly308Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,010 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: OLFM2 NM_058164.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058164.4. 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
	OLFM2	NM_058164.4	MANE Select	c.922G>A	p.Gly308Ser	missense	Exon 6 of 6	NP_477512.1	O95897
	OLFM2	NM_001304347.2		c.994G>A	p.Gly332Ser	missense	Exon 6 of 6	NP_001291276.1	K7EKW2
	OLFM2	NM_001304348.2		c.688G>A	p.Gly230Ser	missense	Exon 5 of 5	NP_001291277.1	K7EIS8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OLFM2	ENST00000264833.9	TSL:1 MANE Select	c.922G>A	p.Gly308Ser	missense	Exon 6 of 6	ENSP00000264833.3	O95897
	OLFM2	ENST00000593091.2	TSL:5	c.994G>A	p.Gly332Ser	missense	Exon 6 of 6	ENSP00000465809.2	K7EKW2
	OLFM2	ENST00000971550.1		c.913G>A	p.Gly305Ser	missense	Exon 6 of 6	ENSP00000641609.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251314 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461818 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111976

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.086	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.65		Gain of sheet (P = 0.0221)
MVP		0.74
MPC		1.7
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.74
Mutation Taster		=40/60	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: rs773856461; hg19: chr19-9965305; COSMIC: COSV53434304; COSMIC: COSV53434304;