rs1057519868

Variant names:

• chr10-103090988-T-G
• rs1057519868
• NM_001351169.2:c.1220A>C

Variant summary

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

The ENST00000404739.8(NT5C2):​c.1220A>C​(p.Asp407Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NT5C2 ENST00000404739.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.65
• Publications: 7 publications found

Genes affected

NT5C2 (HGNC:8022): (5'-nucleotidase, cytosolic II) This gene encodes a hydrolase that serves as an important role in cellular purine metabolism by acting primarily on inosine 5'-monophosphate and other purine nucleotides. [provided by RefSeq, Oct 2011]

NT5C2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 45

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet

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, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000404739.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5C2	NM_001351169.2	MANE Select	c.1220A>C	p.Asp407Ala	missense	Exon 17 of 19	NP_001338098.1
	NT5C2	NM_001351170.2		c.1244A>C	p.Asp415Ala	missense	Exon 17 of 19	NP_001338099.1
	NT5C2	NM_001351171.2		c.1244A>C	p.Asp415Ala	missense	Exon 18 of 20	NP_001338100.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5C2	ENST00000404739.8	TSL:1 MANE Select	c.1220A>C	p.Asp407Ala	missense	Exon 17 of 19	ENSP00000383960.3
	NT5C2	ENST00000343289.9	TSL:1	c.1220A>C	p.Asp407Ala	missense	Exon 16 of 18	ENSP00000339479.5
	NT5C2	ENST00000674860.1		c.1244A>C	p.Asp415Ala	missense	Exon 19 of 21	ENSP00000502816.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.073	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.65		Gain of helix (P = 0.0128)
MVP		0.69
MPC		1.8
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.90
Mutation Taster		=43/57	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: rs1057519868; hg19: chr10-104850745; COSMIC: COSV58417579;