1-183292798-A-T

Variant names:

• chr1-183292798-A-T
• rs202167780
• NM_015039.4:c.234T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_015039.4(NMNAT2):​c.234T>A​(p.Asp78Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NMNAT2 NM_015039.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.156
• Publications: 0 publications found

Genes affected

NMNAT2 (HGNC:16789): (nicotinamide nucleotide adenylyltransferase 2) This gene product belongs to the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyze an essential step in NAD (NADP) biosynthetic pathway. Unlike the other human family member, which is localized to the nucleus, and is ubiquitously expressed; this enzyme is cytoplasmic, and is predominantly expressed in the brain. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1005 (below the threshold of 3.09). Trascript score misZ: 2.0325 (below the threshold of 3.09).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT2	NM_015039.4	c.234T>A	p.Asp78Glu	missense_variant	Exon 3 of 11	ENST00000287713.7	NP_055854.1
NMNAT2	NM_170706.4	c.219T>A	p.Asp73Glu	missense_variant	Exon 3 of 11		NP_733820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMNAT2	ENST00000287713.7	c.234T>A	p.Asp78Glu	missense_variant	Exon 3 of 11	1	NM_015039.4	ENSP00000287713.6
NMNAT2	ENST00000294868.8	c.219T>A	p.Asp73Glu	missense_variant	Exon 3 of 11	1		ENSP00000294868.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.234T>A (p.D78E) alteration is located in exon 3 (coding exon 3) of the NMNAT2 gene. This alteration results from a T to A substitution at nucleotide position 234, causing the aspartic acid (D) at amino acid position 78 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	5.4
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Benign	1.6	.;L
PhyloP100		-0.16
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.082	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.42	B;B
Vest4		0.82
MutPred		0.46		.;Gain of catalytic residue at D78 (P = 0.1663);
MVP		0.94
MPC		0.80
ClinPred		0.36	T
GERP RS		-4.9
Varity_R		0.14
gMVP		0.68
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: rs202167780; hg19: chr1-183261933;