rs2275007

Variant names:

• chr14-20452091-T-A
• rs2275007
• NM_017807.4:c.294A>T

Your query was ambiguous. Multiple possible variants found:

• chr14-20452091-T-A
• chr14-20452091-T-C
• chr14-20452091-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_017807.4(OSGEP):​c.294A>T​(p.Gln98His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q98Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OSGEP NM_017807.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708
• Publications: 40 publications found

Genes affected

OSGEP (HGNC:18028): (O-sialoglycoprotein endopeptidase) Predicted to enable N(6)-L-threonylcarbamoyladenine synthase activity and metal ion binding activity. Involved in tRNA threonylcarbamoyladenosine modification. Located in cytoplasm; nuclear speck; and plasma membrane. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 3. [provided by Alliance of Genome Resources, Apr 2022]

OSGEP Gene-Disease associations (from GenCC):

• Galloway-Mowat syndrome 3

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258515 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.75927 (below the threshold of 3.09). Trascript score misZ: 1.0429 (below the threshold of 3.09). GenCC associations: The gene is linked to Galloway-Mowat syndrome 3, Galloway-Mowat syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSGEP	NM_017807.4	c.294A>T	p.Gln98His	missense_variant	Exon 3 of 11	ENST00000206542.9	NP_060277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSGEP	ENST00000206542.9	c.294A>T	p.Gln98His	missense_variant	Exon 3 of 11	1	NM_017807.4	ENSP00000206542.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151950 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250734 AF XY: 0.00000738

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461504 Hom.: 0 Cov.: 47 AF XY: 0.00000138 AC XY: 1 AN XY: 727048

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111916

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151950 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74198

African (AFR) AF: 0.0000242 AC: 1 AN: 41322

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 118316

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.85
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.0	M;.
PhyloP100		0.71
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.40
Sift	Benign	0.058	T;T
Sift4G	Benign	0.13	T;.
Polyphen		0.99	D;.
Vest4		0.80
MutPred		0.57		Loss of catalytic residue at Q98 (P = 0.0276);Loss of catalytic residue at Q98 (P = 0.0276);
MVP		0.27
MPC		0.74
ClinPred		0.60	D
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.73
gMVP		0.80
Mutation Taster		=42/58	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: rs2275007; hg19: chr14-20920250;