rs1554843434

Variant names:

• chr10-100529408-A-G
• rs1554843434
• NM_005004.4:c.184T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_005004.4(NDUFB8):​c.184T>C​(p.Tyr62His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDUFB8 NM_005004.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.26
• Publications: 0 publications found

Genes affected

NDUFB8 (HGNC:7703): (NADH:ubiquinone oxidoreductase subunit B8) Involved in mitochondrial respiratory chain complex I assembly. Located in endoplasmic reticulum and mitochondrion. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency 32. Biomarker of Alzheimer's disease and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255339 (HGNC:):

HIF1AN (HGNC:17113): (hypoxia inducible factor 1 subunit alpha inhibitor) Enables several functions, including 2-oxoglutarate-dependent dioxygenase activity; NF-kappaB binding activity; and transition metal ion binding activity. Involved in several processes, including negative regulation of Notch signaling pathway; negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; and protein hydroxylation. Located in cytosol; nucleoplasm; and perinuclear region of cytoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 10-100529408-A-G is Pathogenic according to our data. Variant chr10-100529408-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 548134.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005004.4. 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
	NDUFB8	NM_005004.4	MANE Select	c.184T>C	p.Tyr62His	missense	Exon 2 of 5	NP_004995.1	O95169-1
	NDUFB8	NM_001284367.2		c.184T>C	p.Tyr62His	missense	Exon 2 of 5	NP_001271296.1	O95169-2
	NDUFB8	NM_001284368.1		c.91T>C	p.Tyr31His	missense	Exon 2 of 5	NP_001271297.1	O95169-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB8	ENST00000299166.9	TSL:1 MANE Select	c.184T>C	p.Tyr62His	missense	Exon 2 of 5	ENSP00000299166.4	O95169-1
	ENSG00000255339	ENST00000557395.5	TSL:2	n.184T>C		non_coding_transcript_exon	Exon 2 of 10	ENSP00000456832.1
	NDUFB8	ENST00000937696.1		c.184T>C	p.Tyr62His	missense	Exon 2 of 5	ENSP00000607755.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460274 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726428

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111458

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 32 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.72		Loss of phosphorylation at Y62 (P = 0.0098)
MVP		0.68
MPC		1.0
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.022	Neutral
Varity_R		0.91
gMVP		0.88
Mutation Taster		=145/155	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554843434; hg19: chr10-102289165;