NM_182977.3:c.80G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182977.3(NNT):​c.80G>A​(p.Arg27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000944 in 1,613,974 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (10 hom.)
• Consequence: NNT NM_182977.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.902
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039408505).
• BP6: Variant 5-43609275-G-A is Benign according to our data. Variant chr5-43609275-G-A is described in ClinVar as Benign. ClinVar VariationId is 703892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00478 (728/152254) while in subpopulation AFR AF = 0.0157 (654/41548). AF 95% confidence interval is 0.0147. There are 5 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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>A	p.Arg27His	missense	Exon 2 of 22	NP_892022.2	Q13423
	NNT	NM_001331026.2		c.-84G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	NP_001317955.1	E9PCX7
	NNT	NM_012343.4		c.80G>A	p.Arg27His	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>A	p.Arg27His	missense	Exon 2 of 22	ENSP00000343873.4	Q13423
	NNT	ENST00000264663.9	TSL:1	c.80G>A	p.Arg27His	missense	Exon 2 of 22	ENSP00000264663.5	Q13423
	NNT	ENST00000657172.1		c.-658G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	ENSP00000499431.1	A0A590UJI3

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 723 AN: 152136 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00125 AC: 314 AN: 251452 AF XY: 0.000883

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000545 AC: 796 AN: 1461720 Hom.: 10 Cov.: 32 AF XY: 0.000454 AC XY: 330 AN XY: 727170

African (AFR) AF: 0.0174 AC: 584 AN: 33472

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111880

Other (OTH) AF: 0.00162 AC: 98 AN: 60390

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152254 Hom.: 5 Cov.: 32 AF XY: 0.00476 AC XY: 354 AN XY: 74446

African (AFR) AF: 0.0157 AC: 654 AN: 41548

American (AMR) AF: 0.00163 AC: 25 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00161 Hom.: 5

Bravo AF: 0.00580

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00162 AC: 197

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glucocorticoid deficiency 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0039	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.90
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.050	N
REVEL	Uncertain	0.31
Sift	Benign	0.37	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.054
MVP		0.65
MPC		0.32
ClinPred		0.0013	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.32
Mutation Taster		=100/0	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; COSMIC: COSV105099081; COSMIC: COSV105099081;