6-85489525-T-C

Variant names:

• chr6-85489525-T-C
• rs2229524
• NM_002526.4:c.1136T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002526.4(NT5E):​c.1136T>C​(p.Met379Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,612,932 control chromosomes in the GnomAD database, including 8,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (3178 hom., cov: 32)
  • Exomes 𝑓: 0.069 (5418 hom.)
• Consequence: NT5E NM_002526.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.682
• Publications: 21 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028433502).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.366 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.1136T>C	p.Met379Thr	missense	Exon 6 of 9	NP_002517.1	P21589-1
	NT5E	NM_001204813.2		c.1136T>C	p.Met379Thr	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.1136T>C	p.Met379Thr	missense	Exon 6 of 9	ENSP00000257770.3	P21589-1
	NT5E	ENST00000880507.1		c.1310T>C	p.Met437Thr	missense	Exon 7 of 10	ENSP00000550566.1
	NT5E	ENST00000880506.1		c.1160T>C	p.Met387Thr	missense	Exon 6 of 9	ENSP00000550565.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22970 AN: 151988 Hom.: 3171 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0987

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.0525

Gnomad SAS AF: 0.0942

Gnomad FIN AF: 0.0597

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.0851 AC: 21367 AN: 251136 AF XY: 0.0810

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.0847

Gnomad EAS exome AF: 0.0647

Gnomad FIN exome AF: 0.0590

Gnomad NFE exome AF: 0.0618

Gnomad OTH exome AF: 0.0721

GnomAD4 exome AF: 0.0692 AC: 101017 AN: 1460826 Hom.: 5418 Cov.: 35 AF XY: 0.0687 AC XY: 49950 AN XY: 726756

African (AFR) AF: 0.383 AC: 12804 AN: 33406

American (AMR) AF: 0.0602 AC: 2692 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0892 AC: 2331 AN: 26130

East Asian (EAS) AF: 0.0526 AC: 2085 AN: 39668

South Asian (SAS) AF: 0.0799 AC: 6892 AN: 86224

European-Finnish (FIN) AF: 0.0580 AC: 3098 AN: 53402

Middle Eastern (MID) AF: 0.0765 AC: 441 AN: 5764

European-Non Finnish (NFE) AF: 0.0590 AC: 65524 AN: 1111168

Other (OTH) AF: 0.0853 AC: 5150 AN: 60350

GnomAD4 genome AF: 0.151 AC: 23011 AN: 152106 Hom.: 3178 Cov.: 32 AF XY: 0.148 AC XY: 10990 AN XY: 74364

African (AFR) AF: 0.371 AC: 15379 AN: 41472

American (AMR) AF: 0.0985 AC: 1504 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0878 AC: 305 AN: 3472

East Asian (EAS) AF: 0.0527 AC: 272 AN: 5166

South Asian (SAS) AF: 0.0928 AC: 447 AN: 4818

European-Finnish (FIN) AF: 0.0597 AC: 633 AN: 10596

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0610 AC: 4148 AN: 67992

Other (OTH) AF: 0.119 AC: 250 AN: 2108

Alfa AF: 0.0866 Hom.: 3587

Bravo AF: 0.163

TwinsUK AF: 0.0612 AC: 227

ALSPAC AF: 0.0576 AC: 222

ESP6500AA AF: 0.364 AC: 1603

ESP6500EA AF: 0.0685 AC: 589

ExAC AF: 0.0909 AC: 11036

Asia WGS AF: 0.0790 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.38	N
PhyloP100		0.68
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.062
Sift	Benign	0.61	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.095
MPC		0.20
ClinPred		0.0021	T
GERP RS		-0.33
Varity_R		0.068
gMVP		0.70
Mutation Taster		=98/2	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: rs2229524; hg19: chr6-86199243; COSMIC: COSV57629612;