rs1852111919

Variant names:

• chr10-100529485-A-G
• rs1852111919
• NM_005004.4:c.107T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005004.4(NDUFB8):​c.107T>C​(p.Met36Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB8 NM_005004.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial (size 157) in uniprot entity NDUB8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005004.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4	c.107T>C	p.Met36Thr	missense_variant	Exon 2 of 5	ENST00000299166.9	NP_004995.1
NDUFB8	NM_001284367.2	c.107T>C	p.Met36Thr	missense_variant	Exon 2 of 5		NP_001271296.1
NDUFB8	NM_001284368.1	c.14T>C	p.Met5Thr	missense_variant	Exon 2 of 5		NP_001271297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB8	ENST00000299166.9	c.107T>C	p.Met36Thr	missense_variant	Exon 2 of 5	1	NM_005004.4	ENSP00000299166.4
ENSG00000255339	ENST00000557395.5	n.107T>C		non_coding_transcript_exon_variant	Exon 2 of 10	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.107T>C (p.M36T) alteration is located in exon 2 (coding exon 2) of the NDUFB8 gene. This alteration results from a T to C substitution at nucleotide position 107, causing the methionine (M) at amino acid position 36 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Benign	0.097	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.71	T;T;.
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.0	M;.;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.093	B;.;.
Vest4		0.63
MutPred		0.59		Gain of phosphorylation at M36 (P = 0.0203);.;Gain of phosphorylation at M36 (P = 0.0203);
MVP		0.48
MPC		0.38
ClinPred		0.82	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.19
gMVP		0.35

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: rs1852111919; hg19: chr10-102289242;