NM_182977.3:c.80G>C

Variant names:

• chr5-43609275-G-C
• rs34241095
• NM_182977.3:c.80G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182977.3(NNT):​c.80G>C​(p.Arg27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NNT NM_182977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.902
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046199083).

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.80G>C	p.Arg27Pro	missense	Exon 2 of 22	NP_892022.2	Q13423
	NNT	NM_001331026.2		c.-84G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	NP_001317955.1	E9PCX7
	NNT	NM_012343.4		c.80G>C	p.Arg27Pro	missense	Exon 2 of 22	NP_036475.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNT	ENST00000344920.9	TSL:1 MANE Select	c.80G>C	p.Arg27Pro	missense	Exon 2 of 22	ENSP00000343873.4	Q13423
	NNT	ENST00000264663.9	TSL:1	c.80G>C	p.Arg27Pro	missense	Exon 2 of 22	ENSP00000264663.5	Q13423
	NNT	ENST00000657172.1		c.-658G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	ENSP00000499431.1	A0A590UJI3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	11
DANN	Benign	0.14
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	-0.81	N
PhyloP100		0.90
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.39
Sift	Benign	0.93	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.34		Loss of MoRF binding (P = 5e-04)
MVP		0.38
MPC		0.37
ClinPred		0.045	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.44
Mutation Taster		=95/5	polymorphism

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: rs34241095; hg19: chr5-43609377;