11-71464130-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PS1_Moderate PP3 BP4_Moderate

The NM_018161.5(NADSYN1):c.395G>T(p.Trp132Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,609,672 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: NADSYN1 NM_018161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.42

Genes affected

NADSYN1 (HGNC:29832): (NAD synthetase 1) Nicotinamide adenine dinucleotide (NAD) is a coenzyme in metabolic redox reactions, a precursor for several cell signaling molecules, and a substrate for protein posttranslational modifications. NAD synthetase (EC 6.3.5.1) catalyzes the final step in the biosynthesis of NAD from nicotinic acid adenine dinucleotide (NaAD).[supplied by OMIM, Apr 2004]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PS1: Transcript NM_018161.5 (NADSYN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.14511839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NADSYN1	NM_018161.5	c.395G>T	p.Trp132Leu	missense_variant	5/21	ENST00000319023.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NADSYN1	ENST00000319023.7	c.395G>T	p.Trp132Leu	missense_variant	5/21	1	NM_018161.5	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000513 AC: 124 AN: 241556 Hom.: 1 AF XY: 0.000421 AC XY: 55 AN XY: 130646

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000641

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.000117 AC: 170 AN: 1457310 Hom.: 1 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 724412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74518

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000310

ExAC AF: 0.000255 AC: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital NAD deficiency disorder Pathogenic:1

Pathogenic, no assertion criteria provided

research

Embryology Laboratory, Victor Chang Cardiac Research Institute

Dec 01, 2019

This variant, c.395G>T, was found in compound heterozygosity with the pathogenic variant c.145T>C -

NADSYN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2023

The NADSYN1 c.395G>T variant is predicted to result in the amino acid substitution p.Trp132Leu. This variant has been reported in the compound heterozygous state in an individual with NAD deficiency (Szot et al. 2020. PubMed ID: 31883644). Functional assays in this same report showed that the p.Trp132Leu substitution causes a decrease in enzymatic activity of the protein (Szot et al. 2020. PubMed ID: 31883644). This variant is reported in 0.32% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71175176-G-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	28
Dann	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.15	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.96
MPC		0.94
ClinPred		0.81	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs189928649; hg19: chr11-71175176;