chr11-71464130-G-T

Variant names:

• chr11-71464130-G-T
• rs189928649
• NM_018161.5:c.395G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PS1_Moderate PP3 BP4_Moderate BS1_Supporting

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 the same amino acid substitution has been previously reported as Likely pathogenic in 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, multiple submitters, no conflicts P:1 U:2
• 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

Our verdict: Uncertain_significance. The variant received 0 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 8: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.14511839).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000117 (170/1457310) while in subpopulation AMR AF = 0.00301 (133/44210). AF 95% confidence interval is 0.00259. There are 1 homozygotes in GnomAdExome4. There are 84 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NADSYN1	NM_018161.5	c.395G>T	p.Trp132Leu	missense_variant	Exon 5 of 21	ENST00000319023.7	NP_060631.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NADSYN1	ENST00000319023.7	c.395G>T	p.Trp132Leu	missense_variant	Exon 5 of 21	1	NM_018161.5	ENSP00000326424.2

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

GnomAD2 exomes AF: 0.000513 AC: 124 AN: 241556 AF XY: 0.000421

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 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 AC: 0 AN: 33434

Gnomad4 AMR exome AF: 0.00301 AC: 133 AN: 44210

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26042

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39594

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85154

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52682

Gnomad4 NFE exome AF: 0.0000279 AC: 31 AN: 1110194

Gnomad4 Remaining exome AF: 0.0000996 AC: 6 AN: 60236

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 AC: 0.0000240466 AN: 0.0000240466

Gnomad4 AMR AF: 0.00137 AC: 0.00137147 AN: 0.00137147

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000441 AC: 0.0000440969 AN: 0.0000440969

Gnomad4 OTH AF: 0.000473 AC: 0.000473037 AN: 0.000473037

Alfa AF: 0.0000881 Hom.: 0

Bravo AF: 0.000310

ExAC AF: 0.000255 AC: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital NAD deficiency disorder Pathogenic:1

Dec 01, 2019

Embryology Laboratory, Victor Chang Cardiac Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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

NADSYN1-related disorder Uncertain:1

Mar 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:1

Dec 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with reduced protein expression and activity (PMID: 31883644); Observed with a variant on the opposite allele (in trans) in a patient in published literature (PMID: 35491967); Observed with a variant on the opposite allele (in trans) in a fetus in published literature (PMID: 31883644); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35491967, 31883644, 36951206, 37300479) -

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
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
Mutation Taster		=24/76	disease causing (ClinVar)

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;