5-43609241-C-T

Variant names:

• chr5-43609241-C-T
• rs10057103
• NM_182977.3:c.46C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182977.3(NNT):​c.46C>T​(p.Leu16Leu) 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:5
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NNT	NM_182977.3	c.46C>T	p.Leu16Leu	synonymous_variant	Exon 2 of 22	ENST00000344920.9	NP_892022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NNT	ENST00000344920.9	c.46C>T	p.Leu16Leu	synonymous_variant	Exon 2 of 22	1	NM_182977.3	ENSP00000343873.4

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

GnomAD2 exomes AF: 0.519 AC: 130408 AN: 251364 AF XY: 0.522

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 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 AC: 30195 AN: 33476

Gnomad4 AMR exome AF: 0.349 AC: 15614 AN: 44712

Gnomad4 ASJ exome AF: 0.629 AC: 16436 AN: 26128

Gnomad4 EAS exome AF: 0.235 AC: 9319 AN: 39684

Gnomad4 SAS exome AF: 0.510 AC: 43974 AN: 86212

Gnomad4 FIN exome AF: 0.509 AC: 27174 AN: 53410

Gnomad4 NFE exome AF: 0.566 AC: 628547 AN: 1111380

Gnomad4 Remaining exome AF: 0.572 AC: 34528 AN: 60374

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 AC: 0.887154 AN: 0.887154

Gnomad4 AMR AF: 0.485 AC: 0.485069 AN: 0.485069

Gnomad4 ASJ AF: 0.611 AC: 0.611175 AN: 0.611175

Gnomad4 EAS AF: 0.220 AC: 0.220031 AN: 0.220031

Gnomad4 SAS AF: 0.486 AC: 0.486296 AN: 0.486296

Gnomad4 FIN AF: 0.512 AC: 0.51176 AN: 0.51176

Gnomad4 NFE AF: 0.567 AC: 0.567329 AN: 0.567329

Gnomad4 OTH AF: 0.639 AC: 0.639126 AN: 0.639126

Alfa AF: 0.595 Hom.: 43480

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glucocorticoid deficiency 4 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.1
DANN	Benign	0.57
Mutation Taster		=100/0	polymorphism (auto)

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;