6-85450158-C-G

Variant names:

• chr6-85450158-C-G
• rs2127752774
• NM_002526.4:c.19C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002526.4(NT5E):​c.19C>G​(p.Arg7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,564,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NT5E NM_002526.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0890
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13514578).

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.19C>G	p.Arg7Gly	missense	Exon 1 of 9	NP_002517.1	P21589-1
	NT5E	NM_001204813.2		c.19C>G	p.Arg7Gly	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.19C>G	p.Arg7Gly	missense	Exon 1 of 9	ENSP00000257770.3	P21589-1
	NT5E	ENST00000369646.7	TSL:1	c.19C>G	p.Arg7Gly	missense	Exon 1 of 3	ENSP00000358660.3	Q96B60
	NT5E	ENST00000880507.1		c.19C>G	p.Arg7Gly	missense	Exon 1 of 10	ENSP00000550566.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151594 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000134 AC: 19 AN: 1412700 Hom.: 0 Cov.: 31 AF XY: 0.00000997 AC XY: 7 AN XY: 702096

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32178

American (AMR) AF: 0.0000241 AC: 1 AN: 41556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24606

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36784

South Asian (SAS) AF: 0.00 AC: 0 AN: 82910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5314

European-Non Finnish (NFE) AF: 0.0000147 AC: 16 AN: 1086748

Other (OTH) AF: 0.0000173 AC: 1 AN: 57648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151594 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74078

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2092

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	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.76
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.089
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.075
Sift	Benign	0.19	T
Sift4G	Benign	0.39	T
Polyphen		0.093	B
Vest4		0.074
MutPred		0.44		Loss of methylation at R7 (P = 0.0035)
MVP		0.60
MPC		0.33
ClinPred		0.069	T
GERP RS		1.6
PromoterAI		-0.098	Neutral
Varity_R		0.074
gMVP		0.72
Mutation Taster		=80/20	polymorphism

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: rs2127752774; hg19: chr6-86159876;