19-19516276-C-CG

Position:

• chr19-19516276-C-CG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_Strong PP5_Moderate BS2

The NM_015965.7(NDUFA13):​c.44dupG​(p.Tyr16fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFA13 NM_015965.7 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -2.05

Genes affected

NDUFA13 (HGNC:17194): (NADH:ubiquinone oxidoreductase subunit A13) This gene encodes a subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), which functions in the transfer of electrons from NADH to the respiratory chain. The protein is required for complex I assembly and electron transfer activity. The protein binds the signal transducers and activators of transcription 3 (STAT3) transcription factor, and can function as a tumor suppressor. The human protein purified from mitochondria migrates at approximately 16 kDa. Transcripts originating from an upstream promoter and capable of expressing a protein with a longer N-terminus have been found, but their biological validity has not been determined. [provided by RefSeq, Oct 2009]

ENSG00000258674 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.897 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 19-19516276-C-CG is Pathogenic according to our data. Variant chr19-19516276-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2441769.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA13	NM_015965.7	c.44dupG	p.Tyr16fs	frameshift_variant	1/5	ENST00000507754.9	NP_057049.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA13	ENST00000507754.9	c.44dupG	p.Tyr16fs	frameshift_variant	1/5	1	NM_015965.7	ENSP00000423673.1
ENSG00000258674	ENST00000555938.1	c.44dupG	p.Tyr16fs	frameshift_variant	1/7	2		ENSP00000452549.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461600 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 28 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 05, 2022

- -

Hurthle cell carcinoma of thyroid Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs751852332; hg19: chr19-19627085;