rs775499191

Variant names:

• chr1-183286706-TG-T
• rs775499191
• NM_015039.4:c.403delC

Your query was ambiguous. Multiple possible variants found:

• chr1-183286706-TG-T
• chr1-183286706-TG-TGG

Variant summary

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

The NM_015039.4(NMNAT2):​c.403delC​(p.Gln135SerfsTer42) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,300 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NMNAT2 NM_015039.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT2	NM_015039.4	c.403delC	p.Gln135SerfsTer42	frameshift_variant	Exon 5 of 11	ENST00000287713.7	NP_055854.1
NMNAT2	NM_170706.4	c.388delC	p.Gln130SerfsTer42	frameshift_variant	Exon 5 of 11		NP_733820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMNAT2	ENST00000287713.7	c.403delC	p.Gln135SerfsTer42	frameshift_variant	Exon 5 of 11	1	NM_015039.4	ENSP00000287713.6
NMNAT2	ENST00000294868.8	c.388delC	p.Gln130SerfsTer42	frameshift_variant	Exon 5 of 11	1		ENSP00000294868.4
NMNAT2	ENST00000473046.1	n.273delC		non_coding_transcript_exon_variant	Exon 3 of 5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249410 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460300 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726382

⚠️ 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: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111386

Other (OTH) AF: 0.00 AC: 0 AN: 60346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6

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: rs775499191; hg19: chr1-183255841; COSMIC: COSV54268690;