rs2276360

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018161.5(NADSYN1):c.220G>C(p.Val74Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 1,612,740 control chromosomes in the GnomAD database, including 400,882 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 27972 hom., cov: 32)

Exomes 𝑓: 0.69 ( 372910 hom. )

Consequence

NADSYN1
NM_018161.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.230

Publications

45 publications found

Variant links:

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]

NADSYN1 Gene-Disease associations (from GenCC):

vertebral, cardiac, renal, and limb defects syndrome 3
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital vertebral-cardiac-renal anomalies syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NADSYN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.6351913E-6).

BP6

Variant 11-71458501-G-C is Benign according to our data. Variant chr11-71458501-G-C is described in ClinVar as Benign. ClinVar VariationId is 1248202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018161.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NADSYN1	NM_018161.5	MANE Select	c.220G>C	p.Val74Leu	missense	Exon 3 of 21	NP_060631.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NADSYN1	ENST00000319023.7	TSL:1 MANE Select	c.220G>C	p.Val74Leu	missense	Exon 3 of 21	ENSP00000326424.2	Q6IA69-1
NADSYN1	ENST00000528509.5	TSL:1	n.220G>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000433472.1	E9PKY6
NADSYN1	ENST00000859578.1		c.220G>C	p.Val74Leu	missense	Exon 3 of 22	ENSP00000529637.1

Frequencies

GnomAD3 genomes

AF:

0.582

AC:

88408

AN:

151872

Hom.:

27948

Cov.:

show subpopulations

Gnomad AFR

AF:

0.409

Gnomad AMI

AF:

0.687

Gnomad AMR

AF:

0.502

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.383

Gnomad SAS

AF:

0.211

Gnomad FIN

AF:

0.588

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.744

Gnomad OTH

AF:

0.560

GnomAD2 exomes

AF:

0.566

AC:

142274

AN:

251232

AF XY:

0.561

show subpopulations

Gnomad AFR exome

AF:

0.404

Gnomad AMR exome

AF:

0.486

Gnomad ASJ exome

AF:

0.621

Gnomad EAS exome

AF:

0.390

Gnomad FIN exome

AF:

0.600

Gnomad NFE exome

AF:

0.724

Gnomad OTH exome

AF:

0.603

GnomAD4 exome

AF:

0.694

AC:

1014432

AN:

1460750

Hom.:

372910

Cov.:

AF XY:

0.681

AC XY:

494624

AN XY:

726810

show subpopulations

African (AFR)

AF:

0.384

AC:

12828

AN:

33444

American (AMR)

AF:

0.487

AC:

21772

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.622

AC:

16241

AN:

26114

East Asian (EAS)

AF:

0.347

AC:

13765

AN:

39678

South Asian (SAS)

AF:

0.220

AC:

19008

AN:

86230

European-Finnish (FIN)

AF:

0.606

AC:

32386

AN:

53402

Middle Eastern (MID)

AF:

0.465

AC:

2683

AN:

5764

European-Non Finnish (NFE)

AF:

0.771

AC:

857152

AN:

1111090

Other (OTH)

AF:

0.640

AC:

38597

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

12944

25889

38833

51778

64722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20126

40252

60378

80504

100630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.582

AC:

88479

AN:

151990

Hom.:

27972

Cov.:

AF XY:

0.565

AC XY:

41959

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.410

AC:

16975

AN:

41428

American (AMR)

AF:

0.502

AC:

7662

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.614

AC:

2131

AN:

3470

East Asian (EAS)

AF:

0.384

AC:

1981

AN:

5160

South Asian (SAS)

AF:

0.212

AC:

1021

AN:

4814

European-Finnish (FIN)

AF:

0.588

AC:

6208

AN:

10550

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.744

AC:

50567

AN:

67982

Other (OTH)

AF:

0.554

AC:

1170

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1705

3411

5116

6822

8527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.700

Hom.:

26871

Bravo

AF:

0.579

TwinsUK

AF:

0.774

AC:

2869

ALSPAC

AF:

0.763

AC:

2942

ESP6500AA

AF:

0.426

AC:

1874

ESP6500EA

AF:

0.744

AC:

6393

ExAC

AF:

0.560

AC:

67942

Asia WGS

AF:

0.287

AC:

1001

AN:

3478

EpiCase

AF:

0.749

EpiControl

AF:

0.743

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Vertebral, cardiac, renal, and limb defects syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.20

CADD

Benign

0.10

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.029

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0000026

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-2.4

PhyloP100

0.23

PrimateAI

Uncertain

0.56

PROVEAN

Benign

2.6

REVEL

Uncertain

0.47

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.071

MutPred

0.24

Gain of helix (P = 0.062)

MPC

0.17

ClinPred

0.0039

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.64

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over