rs35201656

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182977.3(NNT):c.188A>G(p.Lys63Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0404 in 1,613,734 control chromosomes in the GnomAD database, including 1,757 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K63I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.034 ( 143 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1614 hom. )

Consequence

NNT
NM_182977.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.31

Publications

18 publications found

Variant links:

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

NNT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040031075).

BP6

Variant 5-43612944-A-G is Benign according to our data. Variant chr5-43612944-A-G is described in ClinVar as Benign. ClinVar VariationId is 1671116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NNT	NM_182977.3	MANE Select	c.188A>G	p.Lys63Arg	missense	Exon 3 of 22	NP_892022.2	Q13423
NNT	NM_012343.4		c.188A>G	p.Lys63Arg	missense	Exon 3 of 22	NP_036475.3
NNT	NM_001331026.2		c.-12-2904A>G		intron	N/A	NP_001317955.1	E9PCX7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NNT	ENST00000344920.9	TSL:1 MANE Select	c.188A>G	p.Lys63Arg	missense	Exon 3 of 22	ENSP00000343873.4	Q13423
NNT	ENST00000264663.9	TSL:1	c.188A>G	p.Lys63Arg	missense	Exon 3 of 22	ENSP00000264663.5	Q13423
NNT	ENST00000653251.1		c.188A>G	p.Lys63Arg	missense	Exon 4 of 23	ENSP00000499281.1	Q13423

Frequencies

GnomAD3 genomes

AF:

0.0344

AC:

5225

AN:

152088

Hom.:

140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00864

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0304

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.0643

Gnomad FIN

AF:

0.0349

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0408

Gnomad OTH

AF:

0.0397

GnomAD2 exomes

AF:

0.0444

AC:

11154

AN:

251436

AF XY:

0.0463

show subpopulations

Gnomad AFR exome

AF:

0.00800

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0330

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0454

GnomAD4 exome

AF:

0.0410

AC:

59978

AN:

1461528

Hom.:

1614

Cov.:

AF XY:

0.0423

AC XY:

30742

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.00654

AC:

219

AN:

33480

American (AMR)

AF:

0.0173

AC:

772

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

956

AN:

26136

East Asian (EAS)

AF:

0.119

AC:

4727

AN:

39696

South Asian (SAS)

AF:

0.0677

AC:

5839

AN:

86250

European-Finnish (FIN)

AF:

0.0342

AC:

1824

AN:

53386

Middle Eastern (MID)

AF:

0.0423

AC:

244

AN:

5766

European-Non Finnish (NFE)

AF:

0.0384

AC:

42676

AN:

1111706

Other (OTH)

AF:

0.0451

AC:

2721

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2824

5648

8472

11296

14120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1590

3180

4770

6360

7950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0344

AC:

5238

AN:

152206

Hom.:

143

Cov.:

AF XY:

0.0351

AC XY:

2610

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00862

AC:

358

AN:

41534

American (AMR)

AF:

0.0303

AC:

463

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3472

East Asian (EAS)

AF:

0.128

AC:

664

AN:

5172

South Asian (SAS)

AF:

0.0652

AC:

314

AN:

4816

European-Finnish (FIN)

AF:

0.0349

AC:

370

AN:

10590

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0408

AC:

2774

AN:

68016

Other (OTH)

AF:

0.0449

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

246

492

739

985

1231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0427

Hom.:

528

Bravo

AF:

0.0322

TwinsUK

AF:

0.0351

AC:

130

ALSPAC

AF:

0.0387

AC:

149

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0420

AC:

361

ExAC

AF:

0.0458

AC:

5566

Asia WGS

AF:

0.121

AC:

420

AN:

3478

EpiCase

AF:

0.0442

EpiControl

AF:

0.0434

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Benign

-0.022

Eigen_PC

Benign

0.0058

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

4.3

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.46

Sift

Benign

0.38

Sift4G

Benign

0.30

Polyphen

0.90

Vest4

0.14

MPC

0.30

ClinPred

0.030

GERP RS

1.9

PromoterAI

-0.0068

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.87

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over