NM_002526.4:c.1126A>G

Variant names:

• chr6-85489515-A-G
• rs2229523
• NM_002526.4:c.1126A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• 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
• Publications: 54 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: Benign. The variant received -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 VariationId is 1175159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

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.1126A>G	p.Thr376Ala	missense	Exon 6 of 9	NP_002517.1	P21589-1
	NT5E	NM_001204813.2		c.1126A>G	p.Thr376Ala	missense	Exon 6 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.1126A>G	p.Thr376Ala	missense	Exon 6 of 9	ENSP00000257770.3	P21589-1
	NT5E	ENST00000880507.1		c.1300A>G	p.Thr434Ala	missense	Exon 7 of 10	ENSP00000550566.1
	NT5E	ENST00000880506.1		c.1150A>G	p.Thr384Ala	missense	Exon 6 of 9	ENSP00000550565.1

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

GnomAD2 exomes AF: 0.732 AC: 183773 AN: 250940 AF XY: 0.730

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 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

African (AFR) AF: 0.933 AC: 31158 AN: 33412

American (AMR) AF: 0.863 AC: 38584 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 20007 AN: 26122

East Asian (EAS) AF: 0.605 AC: 24008 AN: 39656

South Asian (SAS) AF: 0.835 AC: 71998 AN: 86204

European-Finnish (FIN) AF: 0.625 AC: 33349 AN: 53366

Middle Eastern (MID) AF: 0.812 AC: 4673 AN: 5758

European-Non Finnish (NFE) AF: 0.667 AC: 739901 AN: 1109468

Other (OTH) AF: 0.716 AC: 43149 AN: 60284

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

African (AFR) AF: 0.927 AC: 38503 AN: 41518

American (AMR) AF: 0.823 AC: 12575 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2646 AN: 3472

East Asian (EAS) AF: 0.603 AC: 3113 AN: 5164

South Asian (SAS) AF: 0.834 AC: 4016 AN: 4816

European-Finnish (FIN) AF: 0.631 AC: 6662 AN: 10560

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 45996 AN: 67944

Other (OTH) AF: 0.753 AC: 1593 AN: 2116

Alfa AF: 0.707 Hom.: 154685

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary arterial and articular multiple calcification syndrome (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	7.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.045
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.059
Sift	Benign	0.52	T
Sift4G	Benign	0.23	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
Mutation Taster		=100/0	polymorphism (auto)

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: rs2229523; hg19: chr6-86199233; COSMIC: COSV107239729;