chr16-1960711-G-C

Position:

• chr16-1960711-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_004548.3(NDUFB10):​c.131-442G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDUFB10 NM_004548.3 intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.882

Genes affected

NDUFB10 (HGNC:7696): (NADH:ubiquinone oxidoreductase subunit B10) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency 35. [provided by Alliance of Genome Resources, Apr 2022]

NDUFB10 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1960711-G-C is Pathogenic according to our data. Variant chr16-1960711-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 873018.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB10	NM_004548.3	c.131-442G>C		intron_variant		ENST00000268668.11	NP_004539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB10	ENST00000268668.11	c.131-442G>C		intron_variant		1	NM_004548.3	ENSP00000268668.6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex I deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Simons Lab, The University of Queensland

Apr 25, 2020

The NM_004548.3: c.131-442G>C variant has been identified in a single family with two affected siblings with mitochondrial disease and a clinical presentation notable for global developmental delay, poor growth, sensorineural hearing loss, and brain MRI abnormalities, both with early death (Helman et al., In press). RNA sequencing of fibroblasts identified the presence of a cryptic exon in intron 1 of NDUFB10, that includes an in frame stop codon. Differential expression analysis relative to control samples suggested significantly decreased expression. The cryptic exon was found to contain a rare intronic variant, NM_004548.3:c.131-442G>C, that was homozygous in both affected siblings and is absent from population allele frequency databases. Immunoblot and quantitative proteomic analysis of fibroblasts from the older sibling revealed decreased abundance of complex I subunit proteins providing evidence of isolated complex I deficiency. Bi-allelic variants in NDUFB10 have previously been reported in a single individual with infantile-onset mitochondrial disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.50
DANN	Benign	0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1475753965; hg19: chr16-2010712;