NM_005004.4:c.551A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_005004.4(NDUFB8):ā€‹c.551A>Gā€‹(p.Tyr184Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,976 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

NDUFB8
NM_005004.4 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.55
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NDUFB8NM_005004.4 linkc.551A>G p.Tyr184Cys missense_variant Exon 5 of 5 ENST00000299166.9 NP_004995.1 O95169-1
NDUFB8NM_001284368.1 linkc.458A>G p.Tyr153Cys missense_variant Exon 5 of 5 NP_001271297.1 O95169-3
NDUFB8NM_001284367.2 linkc.*242A>G 3_prime_UTR_variant Exon 5 of 5 NP_001271296.1 O95169-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NDUFB8ENST00000299166.9 linkc.551A>G p.Tyr184Cys missense_variant Exon 5 of 5 1 NM_005004.4 ENSP00000299166.4 O95169-1
ENSG00000255339ENST00000557395.5 linkn.*112+130A>G intron_variant Intron 5 of 9 2 ENSP00000456832.1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251480
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461818
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Sep 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.551A>G (p.Y184C) alteration is located in exon 5 (coding exon 5) of the NDUFB8 gene. This alteration results from a A to G substitution at nucleotide position 551, causing the tyrosine (Y) at amino acid position 184 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
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
T;T
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
-0.063
T
MutationAssessor
Pathogenic
3.3
M;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-4.8
D;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.82
MutPred
0.71
Loss of phosphorylation at Y184 (P = 0.0298);.;
MVP
0.78
MPC
0.98
ClinPred
0.99
D
GERP RS
5.0
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.81
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773808077; hg19: chr10-102283604; API