19-54103097-T-C

Variant names:

• chr19-54103097-T-C
• rs254259
• NM_004542.4:c.11-17T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004542.4(NDUFA3):​c.11-17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,608,196 control chromosomes in the GnomAD database, including 254,784 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (23745 hom., cov: 30)
  • Exomes 𝑓: 0.56 (231039 hom.)
• Consequence: NDUFA3 NM_004542.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 27 publications found

Genes affected

NDUFA3 (HGNC:7686): (NADH:ubiquinone oxidoreductase subunit A3) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Part of mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

NDUFA3 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004542.4. 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
	NDUFA3	NM_004542.4	MANE Select	c.11-17T>C		intron	N/A	NP_004533.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA3	ENST00000485876.6	TSL:1 MANE Select	c.11-17T>C		intron	N/A	ENSP00000418438.1
	NDUFA3	ENST00000484103.1	TSL:1	n.221T>C		non_coding_transcript_exon	Exon 1 of 3
	NDUFA3	ENST00000451517.5	TSL:1	n.11-17T>C		intron	N/A	ENSP00000410453.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84284 AN: 151602 Hom.: 23734 Cov.: 30

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.516 AC: 125833 AN: 243980 AF XY: 0.519

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.502

Gnomad EAS exome AF: 0.472

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.571

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.560 AC: 816312 AN: 1456476 Hom.: 231039 Cov.: 38 AF XY: 0.559 AC XY: 405074 AN XY: 724088

African (AFR) AF: 0.609 AC: 20336 AN: 33406

American (AMR) AF: 0.346 AC: 15266 AN: 44080

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 13253 AN: 25950

East Asian (EAS) AF: 0.464 AC: 18341 AN: 39514

South Asian (SAS) AF: 0.490 AC: 41986 AN: 85620

European-Finnish (FIN) AF: 0.531 AC: 28140 AN: 52990

Middle Eastern (MID) AF: 0.485 AC: 2795 AN: 5760

European-Non Finnish (NFE) AF: 0.580 AC: 643137 AN: 1108974

Other (OTH) AF: 0.549 AC: 33058 AN: 60182

GnomAD4 genome AF: 0.556 AC: 84334 AN: 151720 Hom.: 23745 Cov.: 30 AF XY: 0.549 AC XY: 40681 AN XY: 74150

African (AFR) AF: 0.600 AC: 24799 AN: 41344

American (AMR) AF: 0.440 AC: 6702 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 1743 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2428 AN: 5120

South Asian (SAS) AF: 0.497 AC: 2392 AN: 4814

European-Finnish (FIN) AF: 0.526 AC: 5554 AN: 10566

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.574 AC: 38988 AN: 67870

Other (OTH) AF: 0.530 AC: 1118 AN: 2108

Alfa AF: 0.567 Hom.: 98592

Bravo AF: 0.551

Asia WGS AF: 0.497 AC: 1730 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-1.2
PromoterAI		0.0054	Neutral
Mutation Taster		=100/0	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: rs254259; hg19: chr19-54606405; COSMIC: COSV52927611; COSMIC: COSV52927611;