3-179617040-A-G

Position:

• chr3-179617040-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002492.4(NDUFB5):​c.338A>G​(p.Tyr113Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDUFB5 NM_002492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.364

Genes affected

NDUFB5 (HGNC:7700): (NADH:ubiquinone oxidoreductase subunit B5) The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). 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. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ENSG00000288698 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB5	NM_002492.4	c.338A>G	p.Tyr113Cys	missense_variant	4/6	ENST00000259037.8	NP_002483.1
NDUFB5	NM_001199957.2	c.182A>G	p.Tyr61Cys	missense_variant	2/4		NP_001186886.1
NDUFB5	NM_001199958.2	c.338A>G	p.Tyr113Cys	missense_variant	4/5		NP_001186887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB5	ENST00000259037.8	c.338A>G	p.Tyr113Cys	missense_variant	4/6	1	NM_002492.4	ENSP00000259037.3
ENSG00000288698	ENST00000680408.1	n.280+991A>G		intron_variant				ENSP00000506198.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456082 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724876

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.338A>G (p.Y113C) alteration is located in exon 4 (coding exon 4) of the NDUFB5 gene. This alteration results from a A to G substitution at nucleotide position 338, causing the tyrosine (Y) at amino acid position 113 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.;.;.
Eigen	Benign	-0.0023
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.9	M;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.5	D;.;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	D;.;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.63
MutPred		0.79		Loss of ubiquitination at K114 (P = 0.0528);Loss of ubiquitination at K114 (P = 0.0528);.;.;.;
MVP		0.64
MPC		0.78
ClinPred		0.99	D
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-179334828;