10-100526422-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005004.4(NDUFB8):c.445G>A(p.Val149Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,608,702 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (5 hom.)
• Consequence: NDUFB8 NM_005004.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.192

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0092586875).
• BP6: Variant 10-100526422-C-T is Benign according to our data. Variant chr10-100526422-C-T is described in ClinVar as [Benign]. Clinvar id is 1559174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000867 (132/152302) while in subpopulation EAS AF= 0.0222 (115/5178). AF 95% confidence interval is 0.0189. There are 3 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFB8	NM_005004.4	c.445G>A	p.Val149Met	missense_variant	4/5	ENST00000299166.9
NDUFB8	NM_001284367.2	c.445G>A	p.Val149Met	missense_variant	4/5
NDUFB8	NM_001284368.1	c.352G>A	p.Val118Met	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFB8	ENST00000299166.9	c.445G>A	p.Val149Met	missense_variant	4/5	1	NM_005004.4	P1

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 132 AN: 152184 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0222

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00181 AC: 445 AN: 246084 Hom.: 3 AF XY: 0.00161 AC XY: 214 AN XY: 133326

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.000244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0238

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000509 AC: 742 AN: 1456400 Hom.: 5 Cov.: 30 AF XY: 0.000476 AC XY: 345 AN XY: 724712

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0143

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152302 Hom.: 3 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74466

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0222

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000925 Hom.: 3

Bravo AF: 0.000888

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NDUFB8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.4
Dann	Benign	0.80
DEOGEN2	Benign	0.026	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.11	T;T;.
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.52	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.026	B;.;.
Vest4		0.051
MVP		0.081
MPC		0.25
ClinPred		0.018	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs141801241; hg19: chr10-102286179; COSMIC: COSV105158644; COSMIC: COSV105158644;