chr19-5892943-T-C

Position:

• chr19-5892943-T-C

Variant summary

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

The NM_001193375.3(NDUFA11):​c.661A>G​(p.Thr221Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,454,928 control chromosomes in the GnomAD database, including 160,519 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14375 hom., cov: 33)
  • Exomes 𝑓: 0.47 (146144 hom.)
• Consequence: NDUFA11 NM_001193375.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.217

Genes affected

ENSG00000267740 (HGNC:):

NDUFA11 (HGNC:20371): (NADH:ubiquinone oxidoreductase subunit A11) This gene encodes a subunit of the membrane-bound mitochondrial complex I. Complex I is composed of numerous subunits and functions as the NADH-ubiquinol reductase of the mitochondrial electron transport chain. Mutations in this gene are associated with severe mitochondrial complex I deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.473702E-6).
• BP6: Variant 19-5892943-T-C is Benign according to our data. Variant chr19-5892943-T-C is described in ClinVar as [Benign]. Clinvar id is 1182880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-5892943-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA11	NM_001193375.3	c.661A>G	p.Thr221Ala	missense_variant	4/4		NP_001180304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000267740	ENST00000586349.5	c.382+3510A>G		intron_variant		2		ENSP00000466639.1
NDUFA11	ENST00000418389.6	c.661A>G	p.Thr221Ala	missense_variant	4/4	2		ENSP00000389160.1
ENSG00000267740	ENST00000585661.1	c.307+3510A>G		intron_variant		2		ENSP00000467210.1
ENSG00000267740	ENST00000592091.5	n.313+3510A>G		intron_variant		2		ENSP00000465499.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64296 AN: 151848 Hom.: 14364 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.385

GnomAD3 exomes AF: 0.488 AC: 39254 AN: 80516 Hom.: 9992 AF XY: 0.487 AC XY: 20357 AN XY: 41762

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.585

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.672

Gnomad SAS exome AF: 0.467

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.453

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.470 AC: 612107 AN: 1302962 Hom.: 146144 Cov.: 41 AF XY: 0.470 AC XY: 297729 AN XY: 633214

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.576

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.717

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.412

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.457

GnomAD4 genome AF: 0.423 AC: 64334 AN: 151966 Hom.: 14375 Cov.: 33 AF XY: 0.429 AC XY: 31880 AN XY: 74276

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.690

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.387

Alfa AF: 0.445 Hom.: 11162

Bravo AF: 0.425

TwinsUK AF: 0.472 AC: 1751

ALSPAC AF: 0.482 AC: 1857

ExAC AF: 0.354 AC: 5582

Asia WGS AF: 0.525 AC: 1821 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Mitochondrial complex 1 deficiency, nuclear type 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.6
DANN	Benign	0.49
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.77	T
Vest4		0.0070
MPC		0.20
ClinPred		0.014	T
GERP RS		0.31
gMVP		0.050

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1678868; hg19: chr19-5892954;