2-206123338-T-TA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_005006.7(NDUFS1):c.*846_*847insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 132,934 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 30)
  • Failed GnomAD Quality Control
• Consequence: NDUFS1 NM_005006.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.106

Genes affected

NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00254 (337/132934) while in subpopulation EAS AF= 0.017 (78/4596). AF 95% confidence interval is 0.0139. There are 1 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS1	NM_005006.7	c.*846_*847insT		3_prime_UTR_variant	19/19	ENST00000233190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS1	ENST00000233190.11	c.*846_*847insT		3_prime_UTR_variant	19/19	1	NM_005006.7	P1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 334 AN: 132896 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00133

Gnomad AMR AF: 0.00867

Gnomad ASJ AF: 0.000319

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.00255

Gnomad FIN AF: 0.000394

Gnomad MID AF: 0.00379

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00499

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00254 AC: 337 AN: 132934 Hom.: 1 Cov.: 30 AF XY: 0.00248 AC XY: 159 AN XY: 64108

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.000319

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.00234

Gnomad4 FIN AF: 0.000394

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00496

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex I deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leigh syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs58253838; hg19: chr2-206988062;