11-71463406-A-G

Variant names:

• chr11-71463406-A-G
• rs2276362
• NM_018161.5:c.264-26A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018161.5(NADSYN1):​c.264-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,604,516 control chromosomes in the GnomAD database, including 397,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.57 (27351 hom., cov: 31)
  • Exomes 𝑓: 0.69 (369680 hom.)
• Consequence: NADSYN1 NM_018161.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.48
• Publications: 19 publications found

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

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 11-71463406-A-G is Benign according to our data. Variant chr11-71463406-A-G is described in ClinVar as Benign. ClinVar VariationId is 1321836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.739 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.264-26A>G		intron	N/A	NP_060631.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NADSYN1	ENST00000319023.7	TSL:1 MANE Select	c.264-26A>G		intron	N/A	ENSP00000326424.2	Q6IA69-1
	NADSYN1	ENST00000528509.5	TSL:1	n.264-26A>G		intron	N/A	ENSP00000433472.1	E9PKY6
	NADSYN1	ENST00000859578.1		c.264-26A>G		intron	N/A	ENSP00000529637.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86830 AN: 151830 Hom.: 27323 Cov.: 31

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.553

GnomAD2 exomes AF: 0.563 AC: 140738 AN: 249914 AF XY: 0.558

Gnomad AFR exome AF: 0.368

Gnomad AMR exome AF: 0.484

Gnomad ASJ exome AF: 0.621

Gnomad EAS exome AF: 0.387

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.724

Gnomad OTH exome AF: 0.602

GnomAD4 exome AF: 0.693 AC: 1006308 AN: 1452568 Hom.: 369680 Cov.: 30 AF XY: 0.679 AC XY: 491068 AN XY: 723176

African (AFR) AF: 0.346 AC: 11520 AN: 33310

American (AMR) AF: 0.485 AC: 21627 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 16194 AN: 26046

East Asian (EAS) AF: 0.346 AC: 13694 AN: 39630

South Asian (SAS) AF: 0.220 AC: 18929 AN: 86058

European-Finnish (FIN) AF: 0.607 AC: 32382 AN: 53376

Middle Eastern (MID) AF: 0.462 AC: 2658 AN: 5754

European-Non Finnish (NFE) AF: 0.771 AC: 851016 AN: 1103670

Other (OTH) AF: 0.637 AC: 38288 AN: 60106

GnomAD4 genome AF: 0.572 AC: 86906 AN: 151948 Hom.: 27351 Cov.: 31 AF XY: 0.556 AC XY: 41268 AN XY: 74256

African (AFR) AF: 0.374 AC: 15490 AN: 41436

American (AMR) AF: 0.498 AC: 7623 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2130 AN: 3466

East Asian (EAS) AF: 0.382 AC: 1963 AN: 5136

South Asian (SAS) AF: 0.211 AC: 1014 AN: 4812

European-Finnish (FIN) AF: 0.588 AC: 6227 AN: 10586

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50544 AN: 67908

Other (OTH) AF: 0.546 AC: 1152 AN: 2108

Alfa AF: 0.678 Hom.: 47239

Bravo AF: 0.567

Asia WGS AF: 0.285 AC: 995 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Vertebral, cardiac, renal, and limb defects syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0070
DANN	Benign	0.27
PhyloP100		-2.5
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2276362; hg19: chr11-71174452; COSMIC: COSV59812675; COSMIC: COSV59812675;