6-85450452-A-G

Variant names:

• chr6-85450452-A-G
• rs756522878
• NM_002526.4:c.313A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002526.4(NT5E):​c.313A>G​(p.Met105Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,599,344 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 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: NT5E NM_002526.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.35
• Publications: 0 publications found

Genes affected

NT5E (HGNC:8021): (5'-nucleotidase ecto) The protein encoded by this gene is a plasma membrane protein that catalyzes the conversion of extracellular nucleotides to membrane-permeable nucleosides. The encoded protein is used as a determinant of lymphocyte differentiation. Defects in this gene can lead to the calcification of joints and arteries. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

NT5E Gene-Disease associations (from GenCC):

• hereditary arterial and articular multiple calcification syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002526.4. 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
	NT5E	NM_002526.4	MANE Select	c.313A>G	p.Met105Val	missense	Exon 1 of 9	NP_002517.1	P21589-1
	NT5E	NM_001204813.2		c.313A>G	p.Met105Val	missense	Exon 1 of 8	NP_001191742.1	P21589-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5E	ENST00000257770.8	TSL:1 MANE Select	c.313A>G	p.Met105Val	missense	Exon 1 of 9	ENSP00000257770.3	P21589-1
	NT5E	ENST00000369646.7	TSL:1	c.313A>G	p.Met105Val	missense	Exon 1 of 3	ENSP00000358660.3	Q96B60
	NT5E	ENST00000880507.1		c.313A>G	p.Met105Val	missense	Exon 1 of 10	ENSP00000550566.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000867 AC: 19 AN: 219258 AF XY: 0.0000842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000204

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.0000456 AC: 66 AN: 1447078 Hom.: 0 Cov.: 32 AF XY: 0.0000460 AC XY: 33 AN XY: 718092

African (AFR) AF: 0.000120 AC: 4 AN: 33382

American (AMR) AF: 0.000261 AC: 11 AN: 42100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.000228 AC: 19 AN: 83206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51700

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5752

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1106194

Other (OTH) AF: 0.0000835 AC: 5 AN: 59890

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.000392 AC: 6 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.85
MVP		0.98
MPC		0.62
ClinPred		0.75	D
GERP RS		4.3
PromoterAI		0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.92
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: rs756522878; hg19: chr6-86160170;