chr11-71455169-T-C

Variant names:

• chr11-71455169-T-C
• rs769220327
• NM_018161.5:c.145T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_018161.5(NADSYN1):​c.145T>C​(p.Cys49Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000684 in 1,461,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NADSYN1 NM_018161.5 missense, splice_region
• Scores: Splicing: ADA: 0.9304
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.82
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 11-71455169-T-C is Pathogenic according to our data. Variant chr11-71455169-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 869157.Status of the report is criteria_provided_single_submitter, 1 stars.

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.145T>C	p.Cys49Arg	missense splice_region	Exon 2 of 21	NP_060631.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NADSYN1	ENST00000319023.7	TSL:1 MANE Select	c.145T>C	p.Cys49Arg	missense splice_region	Exon 2 of 21	ENSP00000326424.2	Q6IA69-1
	NADSYN1	ENST00000528509.5	TSL:1	n.145T>C		splice_region non_coding_transcript_exon	Exon 2 of 10	ENSP00000433472.1	E9PKY6
	NADSYN1	ENST00000859578.1		c.145T>C	p.Cys49Arg	missense splice_region	Exon 2 of 22	ENSP00000529637.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251032 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461220 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726950

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111680

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital NAD deficiency disorder (1)
1	-	-	Vertebral, cardiac, renal, and limb defects syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.78
Sift	Benign	0.038	D
Sift4G	Uncertain	0.040	D
Polyphen		0.28	B
Vest4		0.93
MutPred		0.73		Gain of disorder (P = 0.0227)
MVP		0.90
MPC		0.62
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.99
gMVP		0.99
Mutation Taster		=39/61	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.90
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: rs769220327; hg19: chr11-71166215;