5-43609300-A-T

Variant names:

• chr5-43609300-A-T
• rs745685714
• NM_182977.3:c.105A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_182977.3(NNT):​c.105A>T​(p.Thr35Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: NNT NM_182977.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.714
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 5-43609300-A-T is Benign according to our data. Variant chr5-43609300-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2874751.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.714 with no splicing effect.

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.105A>T	p.Thr35Thr	synonymous	Exon 2 of 22	NP_892022.2	Q13423
	NNT	NM_012343.4		c.105A>T	p.Thr35Thr	synonymous	Exon 2 of 22	NP_036475.3
	NNT	NM_001331026.2		c.-59A>T		5_prime_UTR	Exon 2 of 21	NP_001317955.1	E9PCX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNT	ENST00000344920.9	TSL:1 MANE Select	c.105A>T	p.Thr35Thr	synonymous	Exon 2 of 22	ENSP00000343873.4	Q13423
	NNT	ENST00000264663.9	TSL:1	c.105A>T	p.Thr35Thr	synonymous	Exon 2 of 22	ENSP00000264663.5	Q13423
	NNT	ENST00000653251.1		c.105A>T	p.Thr35Thr	synonymous	Exon 3 of 23	ENSP00000499281.1	Q13423

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251428 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86254

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.2
DANN	Benign	0.46
PhyloP100		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs745685714; hg19: chr5-43609402;