rs2229523

Positions:

• chr6-85489515-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002526.4(NT5E):​c.1126A>G​(p.Thr376Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,611,060 control chromosomes in the GnomAD database, including 397,207 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.76 (45429 hom., cov: 31)
  • Exomes 𝑓: 0.69 (351778 hom.)
• Consequence: NT5E NM_002526.4 missense
• Clinical Significance: Benign criteria provided, single submitter U:1 B:3
• Conservation: PhyloP100: -0.0450

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.6498304E-7).
• BP6: Variant 6-85489515-A-G is Benign according to our data. Variant chr6-85489515-A-G is described in ClinVar as [Benign]. Clinvar id is 1175159.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-85489515-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NT5E	NM_002526.4	c.1126A>G	p.Thr376Ala	missense_variant	6/9	ENST00000257770.8
NT5E	NM_001204813.2	c.1126A>G	p.Thr376Ala	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NT5E	ENST00000257770.8	c.1126A>G	p.Thr376Ala	missense_variant	6/9	1	NM_002526.4	P1
NT5E	ENST00000369651.7	c.1126A>G	p.Thr376Ala	missense_variant	6/8	2
NT5E	ENST00000416334.5	c.421A>G	p.Thr141Ala	missense_variant	4/5	3
NT5E	ENST00000437581.1	c.214A>G	p.Thr72Ala	missense_variant	3/5	3

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115955 AN: 151954 Hom.: 45368 Cov.: 31

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.752

GnomAD3 exomes AF: 0.732 AC: 183773 AN: 250940 Hom.: 68806 AF XY: 0.730 AC XY: 99000 AN XY: 135612

Gnomad AFR exome AF: 0.934

Gnomad AMR exome AF: 0.869

Gnomad ASJ exome AF: 0.768

Gnomad EAS exome AF: 0.594

Gnomad SAS exome AF: 0.834

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.723

GnomAD4 exome AF: 0.690 AC: 1006827 AN: 1458986 Hom.: 351778 Cov.: 37 AF XY: 0.693 AC XY: 503263 AN XY: 725922

Gnomad4 AFR exome AF: 0.933

Gnomad4 AMR exome AF: 0.863

Gnomad4 ASJ exome AF: 0.766

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.835

Gnomad4 FIN exome AF: 0.625

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.716

GnomAD4 genome AF: 0.763 AC: 116079 AN: 152074 Hom.: 45429 Cov.: 31 AF XY: 0.763 AC XY: 56754 AN XY: 74338

Gnomad4 AFR AF: 0.927

Gnomad4 AMR AF: 0.823

Gnomad4 ASJ AF: 0.762

Gnomad4 EAS AF: 0.603

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.677

Gnomad4 OTH AF: 0.753

Alfa AF: 0.696 Hom.: 67051

Bravo AF: 0.783

TwinsUK AF: 0.655 AC: 2427

ALSPAC AF: 0.652 AC: 2514

ESP6500AA AF: 0.925 AC: 4075

ESP6500EA AF: 0.692 AC: 5955

ExAC AF: 0.734 AC: 89061

Asia WGS AF: 0.740 AC: 2572 AN: 3478

EpiCase AF: 0.691

EpiControl AF: 0.698

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary arterial and articular multiple calcification syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	research	Sayed Lab, Stanford University	Jan 01, 2022	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.22
DANN	Benign	0.42
DEOGEN2	Benign	0.082	.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.022	T;T
MetaRNN	Benign	7.6e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.79	N;N
REVEL	Benign	0.059
Sift	Benign	0.52	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0	.;B
Vest4		0.050
MPC		0.17
ClinPred		0.00026	T
GERP RS		-0.40
Varity_R		0.085
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229523; hg19: chr6-86199233;