rs1801311

chr22-42090719-G-Achr22-42090719-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.918

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]

ACMG classification

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	UniProt
NDUFA6	NM_002490.6	c.26C>T	p.Ala9Val	missense_variant	1/3	ENST00000498737.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57170 AN: 152038 Hom.: 11312 Cov.: 34

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

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.: 58 AF XY: 0.333 AC XY: 242391 AN XY: 727208

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.: 34 AF XY: 0.378 AC XY: 28094 AN XY: 74390

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2019	- -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	13
Dann	Uncertain	0.99
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.46	N
MetaRNN	Benign	0.00018	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.016	P
PrimateAI	Benign	0.35	T
REVEL	Benign	0.094
Vest4		0.13
MPC		0.21
ClinPred		0.053	T
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

Other links and lift over

dbSNP: rs1801311; hg19: chr22-42486723; COSMIC: COSV68911946; COSMIC: COSV68911946;