2-174081972-A-G

Variant names:

• chr2-174081972-A-G
• rs1684864899
• NM_013341.5:c.821T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013341.5(OLA1):​c.821T>C​(p.Leu274Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. L274M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OLA1 NM_013341.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

Genes affected

OLA1 (HGNC:28833): (Obg like ATPase 1) This gene encodes a member of the GTPase protein family. The encoded protein interacts with breast cancer-associated gene 1 (BRCA1) and BRCA1-associated RING domain protein (BARD1), and is involved in centrosome regulation. Overexpression of this gene has been observed in multiple types of cancer and may be associated with poor survival. Pseudogenes of this gene have been defined on chromosomes 17 and 22. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23598006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OLA1	NM_013341.5	c.821T>C	p.Leu274Ser	missense_variant	Exon 8 of 11	ENST00000284719.8	NP_037473.3
OLA1	NM_001328688.2	c.758T>C	p.Leu253Ser	missense_variant	Exon 8 of 11		NP_001315617.1
OLA1	NM_001011708.3	c.347T>C	p.Leu116Ser	missense_variant	Exon 7 of 10		NP_001011708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OLA1	ENST00000284719.8	c.821T>C	p.Leu274Ser	missense_variant	Exon 8 of 11	1	NM_013341.5	ENSP00000284719.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461086 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.821T>C (p.L274S) alteration is located in exon 8 (coding exon 7) of the OLA1 gene. This alteration results from a T to C substitution at nucleotide position 821, causing the leucine (L) at amino acid position 274 to be replaced by a serine (S). 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	0.34
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.088	B;P;.
Vest4		0.55
MutPred		0.58		Loss of sheet (P = 0.0181);.;.;
MVP		0.52
MPC		0.61
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.50
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1684864899; hg19: chr2-174946700;