rs61743028

Positions:

chr8-95052195-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152416.4(NDUFAF6):c.838G>A(p.Val280Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,614,070 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 35 hom. )

Consequence

NDUFAF6
NM_152416.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.34

Variant links:

Genes affected

NDUFAF6 (HGNC:28625): (NADH:ubiquinone oxidoreductase complex assembly factor 6) This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency. [provided by RefSeq, Nov 2011]

NDUFAF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009096205).

BP6

Variant 8-95052195-G-A is Benign according to our data. Variant chr8-95052195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0028 (426/152282) while in subpopulation AMR AF= 0.00549 (84/15296). AF 95% confidence interval is 0.00454. There are 4 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF6	NM_152416.4 linkuse as main transcript	c.838G>A	p.Val280Ile	missense_variant	8/9	ENST00000396124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF6	ENST00000396124.9 linkuse as main transcript	c.838G>A	p.Val280Ile	missense_variant	8/9	2	NM_152416.4	P1	Q330K2-1

Frequencies

GnomAD3 genomes

AF:

0.00280

AC:

426

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00323

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00354

AC:

884

AN:

249396

Hom.:

AF XY:

0.00377

AC XY:

510

AN XY:

135324

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.0143

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00216

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00432

Gnomad OTH exome

AF:

0.00727

GnomAD4 exome

AF:

0.00312

AC:

4556

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

2333

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.00445

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00192

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00553

GnomAD4 genome

AF:

0.00280

AC:

426

AN:

152282

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00323

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00438

Hom.:

Bravo

AF:

0.00350

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00464

AC:

ExAC

AF:

0.00348

AC:

421

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NDUFAF6: BP4, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial complex 1 deficiency, nuclear type 17

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Mitochondrial complex 1 deficiency, nuclear type 17;C5394473:Fanconi renotubular syndrome 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0059

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

.;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0091

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

.;.;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.43

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0050

.;.;B

Vest4

0.27

MVP

0.19

MPC

0.14

ClinPred

0.013

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.046

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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