11-71472428-C-T

Variant names:

• chr11-71472428-C-T
• rs2282621
• NM_018161.5:c.408-21C>T

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.408-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,586,398 control chromosomes in the GnomAD database, including 390,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (26472 hom., cov: 33)
  • Exomes 𝑓: 0.69 (364230 hom.)
• Consequence: NADSYN1 NM_018161.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380
• Publications: 20 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: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-71472428-C-T is Benign according to our data. Variant chr11-71472428-C-T is described in ClinVar as Benign. ClinVar VariationId is 1321838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.737 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.408-21C>T		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.408-21C>T		intron	N/A	ENSP00000326424.2	Q6IA69-1
	NADSYN1	ENST00000528509.5	TSL:1	n.408-21C>T		intron	N/A	ENSP00000433472.1	E9PKY6
	NADSYN1	ENST00000859578.1		c.408-21C>T		intron	N/A	ENSP00000529637.1

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84636 AN: 151606 Hom.: 26466 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.537

GnomAD2 exomes AF: 0.564 AC: 141495 AN: 251066 AF XY: 0.559

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.623

Gnomad EAS exome AF: 0.448

Gnomad FIN exome AF: 0.598

Gnomad NFE exome AF: 0.723

Gnomad OTH exome AF: 0.606

GnomAD4 exome AF: 0.692 AC: 992548 AN: 1434674 Hom.: 364230 Cov.: 29 AF XY: 0.678 AC XY: 485152 AN XY: 715204

African (AFR) AF: 0.300 AC: 9944 AN: 33126

American (AMR) AF: 0.482 AC: 21534 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16176 AN: 25944

East Asian (EAS) AF: 0.410 AC: 16239 AN: 39572

South Asian (SAS) AF: 0.221 AC: 18991 AN: 85962

European-Finnish (FIN) AF: 0.606 AC: 32348 AN: 53344

Middle Eastern (MID) AF: 0.462 AC: 2647 AN: 5728

European-Non Finnish (NFE) AF: 0.770 AC: 836685 AN: 1086736

Other (OTH) AF: 0.637 AC: 37984 AN: 59606

GnomAD4 genome AF: 0.558 AC: 84661 AN: 151724 Hom.: 26472 Cov.: 33 AF XY: 0.541 AC XY: 40138 AN XY: 74128

African (AFR) AF: 0.322 AC: 13321 AN: 41426

American (AMR) AF: 0.493 AC: 7530 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2138 AN: 3462

East Asian (EAS) AF: 0.440 AC: 2265 AN: 5152

South Asian (SAS) AF: 0.214 AC: 1030 AN: 4820

European-Finnish (FIN) AF: 0.585 AC: 6133 AN: 10492

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.743 AC: 50370 AN: 67802

Other (OTH) AF: 0.531 AC: 1117 AN: 2102

Alfa AF: 0.691 Hom.: 44769

Bravo AF: 0.552

Asia WGS AF: 0.313 AC: 1092 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	-0.82
CADD	Benign	3.2
DANN	Benign	0.65
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism (auto)

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: rs2282621; hg19: chr11-71183474; COSMIC: COSV59810150; COSMIC: COSV59810150;