2-37232245-G-C

Position:

chr2-37232245-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144736.5(NDUFAF7):c.195G>C(p.Glu65Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,156 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

NDUFAF7
NM_144736.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

Variant links:

Genes affected

NDUFAF7 (HGNC:28816): (NADH:ubiquinone oxidoreductase complex assembly factor 7) This gene encodes an assembly factor protein which helps in the assembly and stabilization of Complex I, a large multi-subunit enzyme in the mitochondrial respiratory chain. Complex I is involved in several physiological activities in the cell, including metabolite transport and ATP synthesis. The encoded protein is a methyltransferase which methylates Arg85 of a subunit of Complex I in the early stages of its assembly. A pseudogene related to this gene is located on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

NDUFAF7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13645369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF7	NM_144736.5 linkuse as main transcript	c.195G>C	p.Glu65Asp	missense_variant	2/10	ENST00000002125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF7	ENST00000002125.9 linkuse as main transcript	c.195G>C	p.Glu65Asp	missense_variant	2/10	1	NM_144736.5	P1	Q7L592-1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00658

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251464

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1460938

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000827

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000793

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1524866). This variant has not been reported in the literature in individuals affected with NDUFAF7-related conditions. This variant is present in population databases (rs201231332, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 65 of the NDUFAF7 protein (p.Glu65Asp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;.;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.6

M;M;.;.;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.6

D;D;D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0090

D;D;T;D;D

Sift4G

Uncertain

0.038

D;T;T;D;T

Polyphen

1.0

D;D;.;.;.

Vest4

0.74

MutPred

0.40

Loss of phosphorylation at Y62 (P = 0.093);Loss of phosphorylation at Y62 (P = 0.093);.;.;.;

MVP

0.40

MPC

0.078

ClinPred

0.50

GERP RS

3.3

Varity_R

0.47

gMVP

0.78

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