rs371840526

Variant names:

• chr8-144051373-C-G
• rs371840526
• NM_017570.5:c.3820G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-144051373-C-G
• chr8-144051373-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017570.5(OPLAH):​c.3820G>C​(p.Glu1274Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1274V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OPLAH NM_017570.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.333
• Publications: 1 publications found

Genes affected

OPLAH (HGNC:8149): (5-oxoprolinase, ATP-hydrolysing) The protein encoded by this gene acts as a homodimer, using ATP hydrolysis to catalyze the conversion of 5-oxo-L-proline to L-glutamate. Defects in this gene are a cause of 5-oxoprolinase deficiency (OPLAHD). [provided by RefSeq, Jun 2012]

ENSG00000293498 (HGNC:):

SMPD5 (HGNC:52275): (sphingomyelin phosphodiesterase 5 (pseudogene)) Predicted to enable sphingomyelin phosphodiesterase activity. Predicted to be involved in ceramide biosynthetic process and sphingomyelin catabolic process. Predicted to act upstream of or within ceramide metabolic process. Predicted to be located in endoplasmic reticulum membrane and mitochondrial membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2003851).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017570.5. 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
	OPLAH	NM_017570.5	MANE Select	c.3820G>C	p.Glu1274Gln	missense	Exon 27 of 27	NP_060040.1	O14841

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPLAH	ENST00000618853.5	TSL:1 MANE Select	c.3820G>C	p.Glu1274Gln	missense	Exon 27 of 27	ENSP00000480476.1	O14841
	OPLAH	ENST00000894965.1		c.3850G>C	p.Glu1284Gln	missense	Exon 27 of 27	ENSP00000565024.1
	OPLAH	ENST00000919620.1		c.3844G>C	p.Glu1282Gln	missense	Exon 27 of 27	ENSP00000589679.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 239718 AF XY: 0.00

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: 0.00000928

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455354 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724152

African (AFR) AF: 0.00 AC: 0 AN: 32842

American (AMR) AF: 0.00 AC: 0 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 38930

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109644

Other (OTH) AF: 0.00 AC: 0 AN: 60074

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.71
DEOGEN2	Benign	0.053	T
Eigen	Benign	0.093
Eigen_PC	Benign	-0.0085
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.33
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.14
MutPred		0.23		Loss of phosphorylation at S1277 (P = 0.0997)
MVP		0.18
ClinPred		0.29	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.61
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs371840526; hg19: chr8-145106274; COSMIC: COSV66299337; COSMIC: COSV66299337;