rs1801311

Variant names:

• chr22-42090719-G-A
• rs1801311
• NM_002490.6:c.26C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-42090719-G-A
• chr22-42090719-G-C

Variant summary

Our verdict is Benign. The variant received -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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9G) has been classified as Uncertain significance.

• 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:5
• Conservation: PhyloP100: 0.918
• Publications: 73 publications found

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-DT (HGNC:45273): (NDUFA6 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002490.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA6	NM_002490.6	MANE Select	c.26C>T	p.Ala9Val	missense	Exon 1 of 3	NP_002481.3	P56556
	NDUFA6-DT	NR_034118.2		n.-214G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA6	ENST00000498737.8	TSL:1 MANE Select	c.26C>T	p.Ala9Val	missense	Exon 1 of 3	ENSP00000418842.3	P56556
	NDUFA6	ENST00000617763.1	TSL:1	c.104C>T	p.Ala35Val	missense	Exon 1 of 3	ENSP00000482543.1	A0A2Y9D025
	NDUFA6	ENST00000874891.1		c.26C>T	p.Ala9Val	missense	Exon 1 of 3	ENSP00000544950.1

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

GnomAD2 exomes AF: 0.333 AC: 83712 AN: 251308 AF XY: 0.337

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 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

African (AFR) AF: 0.511 AC: 17106 AN: 33480

American (AMR) AF: 0.282 AC: 12592 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10541 AN: 26134

East Asian (EAS) AF: 0.153 AC: 6078 AN: 39700

South Asian (SAS) AF: 0.380 AC: 32785 AN: 86258

European-Finnish (FIN) AF: 0.378 AC: 20151 AN: 53348

Middle Eastern (MID) AF: 0.422 AC: 2433 AN: 5768

European-Non Finnish (NFE) AF: 0.325 AC: 361057 AN: 1111996

Other (OTH) AF: 0.348 AC: 21012 AN: 60396

GnomAD4 genome AF: 0.376 AC: 57256 AN: 152156 Hom.: 11348 Cov.: 34 AF XY: 0.378 AC XY: 28094 AN XY: 74390

African (AFR) AF: 0.497 AC: 20620 AN: 41498

American (AMR) AF: 0.332 AC: 5081 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1356 AN: 3468

East Asian (EAS) AF: 0.150 AC: 774 AN: 5166

South Asian (SAS) AF: 0.382 AC: 1845 AN: 4832

European-Finnish (FIN) AF: 0.383 AC: 4049 AN: 10580

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.329 AC: 22395 AN: 67994

Other (OTH) AF: 0.375 AC: 792 AN: 2114

Alfa AF: 0.346 Hom.: 30111

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Mitochondrial complex I deficiency, nuclear type 33 (1)
-	-	1	NDUFA6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-0.93	T
PhyloP100		0.92
PrimateAI	Benign	0.35	T
REVEL	Benign	0.094
Sift4G	Benign	0.10	T
Vest4		0.13
MPC		0.21
ClinPred		0.053	T
GERP RS		2.4
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.42
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

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