Variant rs121434479 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The ENST00000233627.14(NDUFS7):c.434G>A(p.Arg145His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NDUFS7
ENST00000233627.14 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.14

Variant links:

Genes affected

NDUFS7 (HGNC:7714): (NADH:ubiquinone oxidoreductase core subunit S7) This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]

NDUFS7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a chain NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial (size 174) in uniprot entity NDUS7_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in ENST00000233627.14

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 19-1391144-G-A is Pathogenic according to our data. Variant chr19-1391144-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7682.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS7	NM_024407.5 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant	6/8	ENST00000233627.14	NP_077718.3
NDUFS7	NM_001363602.2 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant	6/8		NP_001350531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS7	ENST00000233627.14 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant	6/8	1	NM_024407.5	ENSP00000233627	P1	O75251-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460292

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726320

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

.;D;D;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.9

H;H;.;H;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.1

D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;D;D;.;.

Vest4

0.95

MutPred

0.74

Gain of phosphorylation at Y146 (P = 0.1154);Gain of phosphorylation at Y146 (P = 0.1154);Gain of phosphorylation at Y146 (P = 0.1154);Gain of phosphorylation at Y146 (P = 0.1154);.;

MVP

0.96

MPC

1.6

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.75

gMVP

0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over