chr1-183284730-A-G

Position:

• chr1-183284730-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015039.4(NMNAT2):​c.509T>C​(p.Val170Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 6.76

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2905485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NMNAT2	NM_015039.4	c.509T>C	p.Val170Ala	missense_variant	6/11	ENST00000287713.7
NMNAT2	NM_170706.4	c.494T>C	p.Val165Ala	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NMNAT2	ENST00000287713.7	c.509T>C	p.Val170Ala	missense_variant	6/11	1	NM_015039.4	P1
NMNAT2	ENST00000294868.8	c.494T>C	p.Val165Ala	missense_variant	6/11	1
NMNAT2	ENST00000473046.1	n.379T>C		non_coding_transcript_exon_variant	4/5	1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.509T>C (p.V170A) alteration is located in exon 6 (coding exon 6) of the NMNAT2 gene. This alteration results from a T to C substitution at nucleotide position 509, causing the valine (V) at amino acid position 170 to be replaced by an alanine (A). 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	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.22	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.035
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.14	.;N
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.50	N;N
REVEL	Uncertain	0.53
Sift	Benign	0.27	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.030	B;B
Vest4		0.30
MutPred		0.53		.;Gain of loop (P = 0.0312);
MVP		0.76
MPC		0.97
ClinPred		0.69	D
GERP RS		5.5
Varity_R		0.077
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-183253865;