5-43612944-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 12/20 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.31

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1671116.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-43612944-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NNT	NM_182977.3	c.188A>G	p.Lys63Arg	missense_variant	3/22	ENST00000344920.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NNT	ENST00000344920.9	c.188A>G	p.Lys63Arg	missense_variant	3/22	1	NM_182977.3	P1

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5225 AN: 152088 Hom.: 140 Cov.: 32

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

GnomAD3 exomes AF: 0.0444 AC: 11154 AN: 251436 Hom.: 360 AF XY: 0.0463 AC XY: 6287 AN XY: 135900

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 SAS exome AF: 0.0672

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.: 31 AF XY: 0.0423 AC XY: 30742 AN XY: 727066

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0366

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.0677

Gnomad4 FIN exome AF: 0.0342

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0451

GnomAD4 genome AF: 0.0344 AC: 5238 AN: 152206 Hom.: 143 Cov.: 32 AF XY: 0.0351 AC XY: 2610 AN XY: 74416

Gnomad4 AFR AF: 0.00862

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.0652

Gnomad4 FIN AF: 0.0349

Gnomad4 NFE AF: 0.0408

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0436 Hom.: 256

Bravo AF: 0.0322

TwinsUK AF: 0.0351 AC: 130

ALSPAC AF: 0.0387 AC: 149

ESP6500AA AF: 0.00999 AC: 44

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.022
Eigen_PC	Benign	0.0058
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T;.;T
MetaRNN	Benign	0.0040	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.90	.;.;P;P
Vest4		0.14
MPC		0.30
ClinPred		0.030	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs35201656; hg19: chr5-43613046; COSMIC: COSV52923726; COSMIC: COSV52923726;