rs886039788

Variant names:

• chr5-43616064-G-A
• rs886039788
• NM_182977.3:c.598G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_182977.3(NNT):​c.598G>A​(p.Gly200Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NNT NM_182977.3 missense, splice_region
• Scores: Splicing: ADA: 0.9530
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.72

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 5-43616064-G-A is Pathogenic according to our data. Variant chr5-43616064-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265842.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NNT	NM_182977.3	c.598G>A	p.Gly200Ser	missense_variant, splice_region_variant	Exon 4 of 22	ENST00000344920.9	NP_892022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NNT	ENST00000344920.9	c.598G>A	p.Gly200Ser	missense_variant, splice_region_variant	Exon 4 of 22	1	NM_182977.3	ENSP00000343873.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glucocorticoid deficiency 4 Pathogenic:1

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GLUCOCORTICOID DEFICIENCY 4 WITH MINERALOCORTICOID DEFICIENCY Pathogenic:1

Oct 11, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.9	.;H;H;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D
Polyphen		0.25	.;B;B;.
Vest4		0.92, 0.93
MutPred		0.79		Loss of ubiquitination at K202 (P = 0.0787);Loss of ubiquitination at K202 (P = 0.0787);Loss of ubiquitination at K202 (P = 0.0787);.;
MVP		0.93
MPC		0.30
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.64
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

Publications

LitVar

Other links and lift over

dbSNP: rs886039788; hg19: chr5-43616166;