5-43609241-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182977.3(NNT):c.46C>T(p.Leu16=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 1,613,168 control chromosomes in the GnomAD database, including 263,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32681 hom., cov: 31)
  • Exomes 𝑓: 0.55 (230728 hom.)
• Consequence: NNT NM_182977.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.126

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-43609241-C-T is Benign according to our data. Variant chr5-43609241-C-T is described in ClinVar as [Benign]. Clinvar id is 1174913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-43609241-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.126 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NNT	NM_182977.3	c.46C>T	p.Leu16=	synonymous_variant	2/22	ENST00000344920.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NNT	ENST00000344920.9	c.46C>T	p.Leu16=	synonymous_variant	2/22	1	NM_182977.3	P1

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95790 AN: 151908 Hom.: 32630 Cov.: 31

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.519 AC: 130408 AN: 251364 Hom.: 37212 AF XY: 0.522 AC XY: 70931 AN XY: 135852

Gnomad AFR exome AF: 0.899

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.213

Gnomad SAS exome AF: 0.507

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.567

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.554 AC: 809760 AN: 1461144 Hom.: 230728 Cov.: 38 AF XY: 0.553 AC XY: 402249 AN XY: 726902

Gnomad4 AFR exome AF: 0.902

Gnomad4 AMR exome AF: 0.349

Gnomad4 ASJ exome AF: 0.629

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.510

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.566

Gnomad4 OTH exome AF: 0.572

GnomAD4 genome AF: 0.631 AC: 95890 AN: 152024 Hom.: 32681 Cov.: 31 AF XY: 0.621 AC XY: 46104 AN XY: 74296

Gnomad4 AFR AF: 0.887

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.611

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.512

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.639

Alfa AF: 0.586 Hom.: 33916

Bravo AF: 0.640

Asia WGS AF: 0.417 AC: 1453 AN: 3478

EpiCase AF: 0.581

EpiControl AF: 0.589

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Glucocorticoid deficiency 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.1
Dann	Benign	0.57

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: rs10057103; hg19: chr5-43609343; COSMIC: COSV52923717; COSMIC: COSV52923717;