rs12187908

Variant names:

• chr5-43609170-T-C
• rs12187908
• NM_182977.3:c.-26T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182977.3(NNT):​c.-26T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,583,958 control chromosomes in the GnomAD database, including 79,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5432 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73911 hom.)
• Consequence: NNT NM_182977.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.312
• Publications: 21 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-43609170-T-C is Benign according to our data. Variant chr5-43609170-T-C is described in ClinVar as Benign. ClinVar VariationId is 1325907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.329 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNT	NM_182977.3	MANE Select	c.-26T>C		5_prime_UTR	Exon 2 of 22	NP_892022.2	Q13423
	NNT	NM_012343.4		c.-26T>C		5_prime_UTR	Exon 2 of 22	NP_036475.3
	NNT	NM_001331026.2		c.-189T>C		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.-26T>C		5_prime_UTR	Exon 2 of 22	ENSP00000343873.4	Q13423
	NNT	ENST00000264663.9	TSL:1	c.-26T>C		5_prime_UTR	Exon 2 of 22	ENSP00000264663.5	Q13423
	NNT	ENST00000653251.1		c.-26T>C		5_prime_UTR	Exon 3 of 23	ENSP00000499281.1	Q13423

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36113 AN: 151920 Hom.: 5434 Cov.: 32

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.0665

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.263 AC: 63154 AN: 240306 AF XY: 0.273

Gnomad AFR exome AF: 0.0558

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.0641

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.313 AC: 447802 AN: 1431920 Hom.: 73911 Cov.: 28 AF XY: 0.312 AC XY: 221368 AN XY: 709486

African (AFR) AF: 0.0545 AC: 1780 AN: 32680

American (AMR) AF: 0.188 AC: 7841 AN: 41808

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 9392 AN: 25252

East Asian (EAS) AF: 0.0956 AC: 3758 AN: 39320

South Asian (SAS) AF: 0.245 AC: 19945 AN: 81306

European-Finnish (FIN) AF: 0.343 AC: 18159 AN: 52944

Middle Eastern (MID) AF: 0.340 AC: 1922 AN: 5660

European-Non Finnish (NFE) AF: 0.336 AC: 367020 AN: 1093750

Other (OTH) AF: 0.304 AC: 17985 AN: 59200

GnomAD4 genome AF: 0.237 AC: 36103 AN: 152038 Hom.: 5432 Cov.: 32 AF XY: 0.236 AC XY: 17517 AN XY: 74334

African (AFR) AF: 0.0631 AC: 2615 AN: 41462

American (AMR) AF: 0.236 AC: 3605 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1231 AN: 3472

East Asian (EAS) AF: 0.0667 AC: 346 AN: 5190

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4824

European-Finnish (FIN) AF: 0.344 AC: 3627 AN: 10554

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22593 AN: 67960

Other (OTH) AF: 0.273 AC: 576 AN: 2110

Alfa AF: 0.301 Hom.: 8121

Bravo AF: 0.224

Asia WGS AF: 0.152 AC: 529 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glucocorticoid deficiency 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.8
DANN	Benign	0.64
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12187908; hg19: chr5-43609272; COSMIC: COSV52925486; COSMIC: COSV52925486;