5-1801432-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1

The NM_004553.6(NDUFS6):​c.15G>A​(p.Met5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,605,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M5V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 36)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

NDUFS6
NM_004553.6 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
NDUFS6 (HGNC:7713): (NADH:ubiquinone oxidoreductase subunit S6) This gene encodes a subunit of the NADH:ubiquinone oxidoreductase (complex I), which is the first enzyme complex in the electron transport chain of mitochondria. This complex functions in the transfer of electrons from NADH to the respiratory chain. The subunit encoded by this gene is one of seven subunits in the iron-sulfur protein fraction. Mutations in this gene cause mitochondrial complex I deficiency, a disease that causes a wide variety of clinical disorders, including neonatal disease and adult-onset neurodegenerative disorders.[provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10948154).
BP6
Variant 5-1801432-G-A is Benign according to our data. Variant chr5-1801432-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2153173.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000213 (31/1452826) while in subpopulation AFR AF= 0.000389 (13/33384). AF 95% confidence interval is 0.00023. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NDUFS6NM_004553.6 linkuse as main transcriptc.15G>A p.Met5Ile missense_variant 1/4 ENST00000274137.10
MRPL36XM_011514080.3 linkuse as main transcriptc.-66C>T 5_prime_UTR_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NDUFS6ENST00000274137.10 linkuse as main transcriptc.15G>A p.Met5Ile missense_variant 1/41 NM_004553.6 P1
NDUFS6ENST00000469176.1 linkuse as main transcriptc.15G>A p.Met5Ile missense_variant 1/32
NDUFS6ENST00000510329.1 linkuse as main transcriptn.12G>A non_coding_transcript_exon_variant 1/23

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152258
Hom.:
0
Cov.:
36
show subpopulations
Gnomad AFR
AF:
0.000241
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:
0.00000880
AC:
2
AN:
227152
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
126170
show subpopulations
Gnomad AFR exome
AF:
0.000148
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000213
AC:
31
AN:
1452826
Hom.:
0
Cov.:
33
AF XY:
0.0000194
AC XY:
14
AN XY:
722680
show subpopulations
Gnomad4 AFR exome
AF:
0.000389
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:
9.01e-7
Gnomad4 OTH exome
AF:
0.000266
GnomAD4 genome
AF:
0.0000656
AC:
10
AN:
152376
Hom.:
0
Cov.:
36
AF XY:
0.0000671
AC XY:
5
AN XY:
74522
show subpopulations
Gnomad4 AFR
AF:
0.000240
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
Bravo
AF:
0.0000567
ExAC
AF:
0.00000840
AC:
1
Asia WGS
AF:
0.000867
AC:
3
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 14, 2022This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 5 of the NDUFS6 protein (p.Met5Ile). This variant is present in population databases (rs374411074, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NDUFS6-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Mitochondrial complex 1 deficiency, nuclear type 9 Benign:1
Likely benign, criteria provided, single submitterclinical testing3billionSep 20, 2024The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
17
DANN
Benign
0.93
DEOGEN2
Benign
0.040
T;.
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.26
N;N
REVEL
Benign
0.13
Sift
Benign
0.42
T;D
Sift4G
Benign
0.57
T;T
Polyphen
0.0
B;.
Vest4
0.17
MutPred
0.36
Loss of disorder (P = 0.0217);Loss of disorder (P = 0.0217);
MVP
0.43
MPC
0.15
ClinPred
0.78
D
GERP RS
3.2
Varity_R
0.27
gMVP
0.30

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

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

Other links and lift over

dbSNP: rs374411074; hg19: chr5-1801546; API