22-42086192-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002490.6(NDUFA6):c.378C>T(p.His126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,190 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: NDUFA6 NM_002490.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.238

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-42086192-G-A is Benign according to our data. Variant chr22-42086192-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1298897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.238 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000972 (148/152314) while in subpopulation SAS AF= 0.00186 (9/4834). AF 95% confidence interval is 0.00138. There are 1 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA6	NM_002490.6	c.378C>T	p.His126=	synonymous_variant	3/3	ENST00000498737.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA6	ENST00000498737.8	c.378C>T	p.His126=	synonymous_variant	3/3	1	NM_002490.6	P1
NDUFA6	ENST00000617763.1	c.456C>T	p.His152=	synonymous_variant	3/3	1
NDUFA6	ENST00000470753.1	c.207C>T	p.His69=	synonymous_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 256 AN: 251488 Hom.: 2 AF XY: 0.00100 AC XY: 136 AN XY: 135922

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00111 AC: 1627 AN: 1461876 Hom.: 4 Cov.: 31 AF XY: 0.00114 AC XY: 831 AN XY: 727242

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000927 AC XY: 69 AN XY: 74468

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00160 Hom.: 1

Bravo AF: 0.000763

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NDUFA6: BP4, BP7, BS2 -

NDUFA6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

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
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.0
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs150607291; hg19: chr22-42482196; COSMIC: COSV58938368; COSMIC: COSV58938368;