1-9943519-A-G

Variant names:

• chr1-9943519-A-G
• rs957312118
• NM_022787.4:c.-57+4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_022787.4(NMNAT1):​c.-57+4A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NMNAT1 NM_022787.4 splice_region, intron
• Scores: Splicing: ADA: 0.9087
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

Genes affected

NMNAT1 (HGNC:17877): (nicotinamide nucleotide adenylyltransferase 1) This gene encodes an enzyme which catalyzes a key step in the biosynthesis of nicotinamide adenine dinucleotide (NAD). The encoded enzyme is one of several nicotinamide nucleotide adenylyltransferases, and is specifically localized to the cell nucleus. Activity of this protein leads to the activation of a nuclear deacetylase that functions in the protection of damaged neurons. Mutations in this gene have been associated with Leber congenital amaurosis 9. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are located on chromosomes 1, 3, 4, 14, and 15. [provided by RefSeq, Jul 2014]

ENSG00000228150 (HGNC:):

LZIC (HGNC:17497): (leucine zipper and CTNNBIP1 domain containing) Predicted to enable beta-catenin binding activity. Predicted to be involved in response to ionizing radiation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-9943519-A-G is Pathogenic according to our data. Variant chr1-9943519-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 978248.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022787.4. 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
	NMNAT1	NM_022787.4	MANE Select	c.-57+4A>G		splice_region intron	N/A	NP_073624.2
	NMNAT1	NM_001297778.1		c.-57+494A>G		intron	N/A	NP_001284707.1	Q9HAN9
	NMNAT1	NM_001297779.2		c.-57+4A>G		splice_region intron	N/A	NP_001284708.1	B1AN62

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMNAT1	ENST00000377205.6	TSL:1 MANE Select	c.-57+4A>G		splice_region intron	N/A	ENSP00000366410.1	Q9HAN9
	NMNAT1	ENST00000887500.1		c.-155+4A>G		splice_region intron	N/A	ENSP00000557559.1
	NMNAT1	ENST00000946962.1		c.-133+4A>G		splice_region intron	N/A	ENSP00000617021.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Leber congenital amaurosis 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Benign	0.70
PhyloP100		3.6
PromoterAI		-0.53	Under-expression

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs957312118; hg19: chr1-10003577;