chr6-85450183-C-T

Variant names:

• chr6-85450183-C-T
• rs780759467
• NM_002526.4:c.44C>T

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.44C>T​(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,454,498 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NT5E NM_002526.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.925
• 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=0.12647685).

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.44C>T	p.Ala15Val	missense	Exon 1 of 9	NP_002517.1	P21589-1
	NT5E	NM_001204813.2		c.44C>T	p.Ala15Val	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.44C>T	p.Ala15Val	missense	Exon 1 of 9	ENSP00000257770.3	P21589-1
	NT5E	ENST00000369646.7	TSL:1	c.44C>T	p.Ala15Val	missense	Exon 1 of 3	ENSP00000358660.3	Q96B60
	NT5E	ENST00000880507.1		c.44C>T	p.Ala15Val	missense	Exon 1 of 10	ENSP00000550566.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1454498 Hom.: 0 Cov.: 32 AF XY: 0.00000968 AC XY: 7 AN XY: 723114

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1109864

Other (OTH) AF: 0.0000166 AC: 1 AN: 60076

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.99	L
PhyloP100		0.93
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.053
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.081
MutPred		0.57		Gain of helix (P = 0.027)
MVP		0.61
MPC		0.38
ClinPred		0.095	T
GERP RS		1.8
PromoterAI		0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.019
gMVP		0.60
Mutation Taster		=92/8	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: rs780759467; hg19: chr6-86159901;