NM_182977.3:c.600-1delG

Variant names:

• chr5-43619030-AG-A
• rs786205344
• NM_182977.3:c.600-1delG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_182977.3(NNT):​c.600-1delG variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NNT NM_182977.3 splice_acceptor, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.00
• Publications: 1 publications found

Genes affected

NNT (HGNC:7863): (nicotinamide nucleotide transhydrogenase) This gene encodes an integral protein of the inner mitochondrial membrane. The enzyme couples hydride transfer between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis and in free radical detoxification. [provided by RefSeq, Sep 2016]

NNT Gene-Disease associations (from GenCC):

• glucocorticoid deficiency 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026985588 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of 6, new splice context is: atttatttttaaattataAGgct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-43619030-AG-A is Pathogenic according to our data. Variant chr5-43619030-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 35539.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182977.3. 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
	NNT	NM_182977.3	MANE Select	c.600-1delG		splice_acceptor intron	N/A	NP_892022.2	Q13423
	NNT	NM_012343.4		c.600-1delG		splice_acceptor intron	N/A	NP_036475.3
	NNT	NM_001331026.2		c.207-1delG		splice_acceptor intron	N/A	NP_001317955.1	E9PCX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNT	ENST00000344920.9	TSL:1 MANE Select	c.600-1delG		splice_acceptor intron	N/A	ENSP00000343873.4	Q13423
	NNT	ENST00000264663.9	TSL:1	c.600-1delG		splice_acceptor intron	N/A	ENSP00000264663.5	Q13423
	NNT	ENST00000653251.1		c.600-1delG		splice_acceptor intron	N/A	ENSP00000499281.1	Q13423

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000911 AC: 12 AN: 1317370 Hom.: 0 Cov.: 24 AF XY: 0.0000122 AC XY: 8 AN XY: 653496

African (AFR) AF: 0.00 AC: 0 AN: 28638

American (AMR) AF: 0.00 AC: 0 AN: 33998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22716

East Asian (EAS) AF: 0.00 AC: 0 AN: 36500

South Asian (SAS) AF: 0.00 AC: 0 AN: 60758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.0000107 AC: 11 AN: 1028784

Other (OTH) AF: 0.0000186 AC: 1 AN: 53668

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Glucocorticoid deficiency 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.92		Position offset: 9
DS_AL_spliceai		0.97		Position offset: 2

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

Other links and lift over

dbSNP: rs786205344; hg19: chr5-43619132;