rs201223057

Positions:

chr8-95025091-G-C

Variant summary

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

The NM_152416.4(NDUFAF6):c.83G>C(p.Gly28Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,481,506 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 11 hom. )

Consequence

NDUFAF6
NM_152416.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.09

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:

NDUFAF6 (HGNC:):

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=0.0051229).

BP6

Variant 8-95025091-G-C is Benign according to our data. Variant chr8-95025091-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 214210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00339 (4504/1329208) while in subpopulation NFE AF= 0.00377 (3994/1058736). AF 95% confidence interval is 0.00367. There are 11 homozygotes in gnomad4_exome. There are 2191 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFAF6	NM_152416.4 linkuse as main transcript	c.83G>C	p.Gly28Ala	missense_variant	1/9	ENST00000396124.9	NP_689629.2	Q330K2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFAF6	ENST00000396124.9 linkuse as main transcript	c.83G>C	p.Gly28Ala	missense_variant	1/9	2	NM_152416.4	ENSP00000379430.4		Q330K2-1

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00334

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00135

AC:

117

AN:

86834

Hom.:

AF XY:

0.00139

AC XY:

AN XY:

50244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000198

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00155

Gnomad FIN exome

AF:

0.00337

Gnomad NFE exome

AF:

0.00190

Gnomad OTH exome

AF:

0.00172

GnomAD4 exome

AF:

0.00339

AC:

4504

AN:

1329208

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

2191

AN XY:

656182

show subpopulations

Gnomad4 AFR exome

AF:

0.000442

Gnomad4 AMR exome

AF:

0.000494

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.00538

Gnomad4 NFE exome

AF:

0.00377

Gnomad4 OTH exome

AF:

0.00280

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152298

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.00334

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.00174

ExAC

AF:

0.000773

AC:

Asia WGS

AF:

0.000579

AC:

AN:

3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	NDUFAF6: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Sep 10, 2021

- -

NDUFAF6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.69

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.12

REVEL

Benign

0.18

Sift

Benign

0.17

Sift4G

Benign

0.80

Polyphen

0.088

Vest4

0.22

MVP

0.088

MPC

0.18

ClinPred

0.024

GERP RS

-0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.033

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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