rs1801311

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002490.6(NDUFA6):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,613,960 control chromosomes in the GnomAD database, including 93,601 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.38 ( 11348 hom., cov: 34)

Exomes 𝑓: 0.33 ( 82253 hom. )

Consequence

NDUFA6
NM_002490.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.918

Variant links:

Genes affected

NDUFA6 (HGNC:7690): (NADH:ubiquinone oxidoreductase subunit A6) This gene encodes a member of the LYR family of proteins that contain a highly conserved tripeptide (LYR) motif near the N-terminus. The encoded protein is an accessory subunit of NADH: ubiquinone oxidorerductase (Complex I), which is the largest enzyme of the mitochondrial membrane respiratory chain. Complex I functions in electron transfer from NADH to the respiratory chain. [provided by RefSeq, Oct 2016]

NDUFA6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.8364191E-4).

BP6

Variant 22-42090719-G-A is Benign according to our data. Variant chr22-42090719-G-A is described in ClinVar as [Benign]. Clinvar id is 1244198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA6	NM_002490.6 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/3	ENST00000498737.8	NP_002481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA6	ENST00000498737.8 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/3	1	NM_002490.6	ENSP00000418842	P1
NDUFA6	ENST00000617763.1 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/3	1		ENSP00000482543

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57170

AN:

152038

Hom.:

11312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.496

Gnomad AMI

AF:

0.216

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.391

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.381

Gnomad FIN

AF:

0.383

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.329

Gnomad OTH

AF:

0.377

GnomAD3 exomes

AF:

0.333

AC:

83712

AN:

251308

Hom.:

14853

AF XY:

0.337

AC XY:

45854

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.504

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.402

Gnomad EAS exome

AF:

0.144

Gnomad SAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.388

Gnomad NFE exome

AF:

0.330

Gnomad OTH exome

AF:

0.351

GnomAD4 exome

AF:

0.331

AC:

483755

AN:

1461804

Hom.:

82253

Cov.:

AF XY:

0.333

AC XY:

242391

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.511

Gnomad4 AMR exome

AF:

0.282

Gnomad4 ASJ exome

AF:

0.403

Gnomad4 EAS exome

AF:

0.153

Gnomad4 SAS exome

AF:

0.380

Gnomad4 FIN exome

AF:

0.378

Gnomad4 NFE exome

AF:

0.325

Gnomad4 OTH exome

AF:

0.348

GnomAD4 genome

AF:

0.376

AC:

57256

AN:

152156

Hom.:

11348

Cov.:

AF XY:

0.378

AC XY:

28094

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.497

Gnomad4 AMR

AF:

0.332

Gnomad4 ASJ

AF:

0.391

Gnomad4 EAS

AF:

0.150

Gnomad4 SAS

AF:

0.382

Gnomad4 FIN

AF:

0.383

Gnomad4 NFE

AF:

0.329

Gnomad4 OTH

AF:

0.375

Alfa

AF:

0.339

Hom.:

20211

Bravo

AF:

0.374

TwinsUK

AF:

0.316

AC:

1171

ALSPAC

AF:

0.316

AC:

1219

ESP6500AA

AF:

0.493

AC:

2174

ESP6500EA

AF:

0.336

AC:

2889

ExAC

AF:

0.337

AC:

40891

Asia WGS

AF:

0.281

AC:

977

AN:

3478

EpiCase

AF:

0.339

EpiControl

AF:

0.345

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial complex 1 deficiency, nuclear type 33

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

NDUFA6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as 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

0.091

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.46

MetaRNN

Benign

0.00018

T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

0.016

PrimateAI

Benign

0.35

REVEL

Benign

0.094

Sift4G

Benign

0.10

.;T

Vest4

0.13

MPC

0.21

ClinPred

0.053

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.42

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