22-42086248-G-A

Position:

• chr22-42086248-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002490.6(NDUFA6):​c.322C>T​(p.His108Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00191 in 1,614,190 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (21 hom.)
• Consequence: NDUFA6 NM_002490.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.60

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=0.007718563).
• BP6: Variant 22-42086248-G-A is Benign according to our data. Variant chr22-42086248-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 218611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0037 (564/152320) while in subpopulation AFR AF= 0.00734 (305/41562). AF 95% confidence interval is 0.00666. There are 2 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA6	NM_002490.6	c.322C>T	p.His108Tyr	missense_variant	3/3	ENST00000498737.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA6	ENST00000498737.8	c.322C>T	p.His108Tyr	missense_variant	3/3	1	NM_002490.6	P1
NDUFA6	ENST00000617763.1	c.400C>T	p.His134Tyr	missense_variant	3/3	1
NDUFA6	ENST00000470753.1	c.151C>T	p.His51Tyr	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 566 AN: 152202 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00289 AC: 727 AN: 251488 Hom.: 3 AF XY: 0.00271 AC XY: 368 AN XY: 135916

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.0315

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00173 AC: 2527 AN: 1461870 Hom.: 21 Cov.: 31 AF XY: 0.00175 AC XY: 1274 AN XY: 727234

Gnomad4 AFR exome AF: 0.00786

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.0307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000798

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152320 Hom.: 2 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74482

Gnomad4 AFR AF: 0.00734

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00328 Hom.: 4

Bravo AF: 0.00407

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	NDUFA6: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jun 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	.;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.0077	T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
REVEL	Benign	0.18
Sift4G	Benign	0.12	.;T;T
Vest4		0.18, 0.21
MVP		0.22
MPC		0.24
ClinPred		0.016	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.50
gMVP		0.71

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: rs113437301; hg19: chr22-42482252;