Genetic Variant NDUFS6:c.186+4139C>T (chr5-1806513-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004553.6(NDUFS6):c.186+4139C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 152,176 control chromosomes in the GnomAD database, including 21,776 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 21776 hom., cov: 34)

Consequence

NDUFS6
NM_004553.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.997

Publications

3 publications found

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]

NDUFS6 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex I deficiency, nuclear type 9
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
mitochondrial complex I deficiency, nuclear type
Inheritance: AR Classification: MODERATE Submitted by: Illumina
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NDUFS6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS6	NM_004553.6 link	c.186+4139C>T		intron_variant	Intron 2 of 3	ENST00000274137.10	NP_004544.1	O75380Q6IBC4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS6	ENST00000274137.10 link	c.186+4139C>T		intron_variant	Intron 2 of 3	1	NM_004553.6	ENSP00000274137.6		O75380
NDUFS6	ENST00000469176.1 link	c.186+4139C>T		intron_variant	Intron 2 of 2	2		ENSP00000422557.1		D6RBT3

Frequencies

GnomAD3 genomes

AF:

0.494

AC:

75124

AN:

152058

Hom.:

21788

Cov.:

show subpopulations

Gnomad AFR

AF:

0.182

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.554

Gnomad ASJ

AF:

0.695

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.506

Gnomad FIN

AF:

0.654

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.646

Gnomad OTH

AF:

0.569

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.494

AC:

75113

AN:

152176

Hom.:

21776

Cov.:

AF XY:

0.494

AC XY:

36757

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.182

AC:

7551

AN:

41484

American (AMR)

AF:

0.553

AC:

8466

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.695

AC:

2410

AN:

3470

East Asian (EAS)

AF:

0.280

AC:

1454

AN:

5190

South Asian (SAS)

AF:

0.506

AC:

2442

AN:

4822

European-Finnish (FIN)

AF:

0.654

AC:

6924

AN:

10580

Middle Eastern (MID)

AF:

0.656

AC:

193

AN:

294

European-Non Finnish (NFE)

AF:

0.646

AC:

43954

AN:

68012

Other (OTH)

AF:

0.566

AC:

1198

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1698

3395

5093

6790

8488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.598

Hom.:

13884

Bravo

AF:

0.473

Asia WGS

AF:

0.390

AC:

1357

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.33

(source)

DANN

Benign

0.64

PhyloP100

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over