chr5-1801434-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004553.6(NDUFS6):​c.17C>T​(p.Thr6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,605,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T6T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 36)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

NDUFS6
NM_004553.6 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.27
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NDUFS6NM_004553.6 linkuse as main transcriptc.17C>T p.Thr6Ile missense_variant 1/4 ENST00000274137.10
MRPL36XM_011514080.3 linkuse as main transcriptc.-68G>A 5_prime_UTR_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NDUFS6ENST00000274137.10 linkuse as main transcriptc.17C>T p.Thr6Ile missense_variant 1/41 NM_004553.6 P1
NDUFS6ENST00000469176.1 linkuse as main transcriptc.17C>T p.Thr6Ile missense_variant 1/32
NDUFS6ENST00000510329.1 linkuse as main transcriptn.14C>T non_coding_transcript_exon_variant 1/23

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152258
Hom.:
0
Cov.:
36
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
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:
0.0000176
AC:
4
AN:
227236
Hom.:
0
AF XY:
0.0000238
AC XY:
3
AN XY:
126198
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:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000298
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000248
AC:
36
AN:
1452854
Hom.:
0
Cov.:
33
AF XY:
0.0000249
AC XY:
18
AN XY:
722714
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000673
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:
0.0000261
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152258
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
74398
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000299
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000840
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 07, 2021The c.17C>T (p.T6I) alteration is located in exon 1 (coding exon 1) of the NDUFS6 gene. This alteration results from a C to T substitution at nucleotide position 17, causing the threonine (T) at amino acid position 6 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 01, 2022This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 6 of the NDUFS6 protein (p.Thr6Ile). This variant is present in population databases (rs754131778, gnomAD 0.003%). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Benign
-0.030
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.079
T;.
Eigen
Benign
0.057
Eigen_PC
Benign
0.062
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.77
T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Uncertain
0.63
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
0.90
D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.5
N;N
REVEL
Uncertain
0.35
Sift
Benign
0.13
T;D
Sift4G
Benign
0.19
T;T
Polyphen
0.48
P;.
Vest4
0.60
MutPred
0.36
Loss of disorder (P = 0.0262);Loss of disorder (P = 0.0262);
MVP
0.77
MPC
0.47
ClinPred
0.93
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.17
gMVP
0.57

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: rs754131778; hg19: chr5-1801548; API