Genetic Variant NDUFS4:c.177+13531A>C (chr5-53617061-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_002495.4(NDUFS4):c.177+13531A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 151,988 control chromosomes in the GnomAD database, including 13,975 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 0.42 ( 13975 hom., cov: 31)

Consequence

NDUFS4
NM_002495.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.58

Publications

8 publications found

Variant links:

Genes affected

NDUFS4 (HGNC:7711): (NADH:ubiquinone oxidoreductase subunit S4) This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

NDUFS4 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex I deficiency, nuclear type 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
mitochondrial complex I deficiency, nuclear type
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NDUFS4 links:

Genome browser will be placed here

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=-0.79).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002495.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDUFS4	NM_002495.4	MANE Select	c.177+13531A>C	intron	N/A	NP_002486.1	A0A0S2Z433
NDUFS4	NM_001318051.2		c.177+13531A>C	intron	N/A	NP_001304980.1
NDUFS4	NR_134473.2		n.373+12166A>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.177+13531A>C	intron	N/A	ENSP00000296684.5	O43181
NDUFS4	ENST00000506974.5	TSL:1	n.349+12166A>C	intron	N/A	ENSP00000425967.1	D6RI09
NDUFS4	ENST00000856911.1		c.349+12166A>C	intron	N/A	ENSP00000526970.1

Frequencies

GnomAD3 genomes

AF:

0.417

AC:

63371

AN:

151870

Hom.:

13957

Cov.:

show subpopulations

Gnomad AFR

AF:

0.560

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.362

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.481

Gnomad SAS

AF:

0.473

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.410

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

GnomAD4 genome

AF:

0.417

AC:

63423

AN:

151988

Hom.:

13975

Cov.:

AF XY:

0.417

AC XY:

30937

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.561

AC:

23225

AN:

41434

American (AMR)

AF:

0.362

AC:

5533

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

1183

AN:

3470

East Asian (EAS)

AF:

0.480

AC:

2478

AN:

5164

South Asian (SAS)

AF:

0.473

AC:

2271

AN:

4804

European-Finnish (FIN)

AF:

0.336

AC:

3541

AN:

10550

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.354

AC:

24084

AN:

67960

Other (OTH)

AF:

0.410

AC:

866

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1816

3633

5449

7266

9082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

592

1184

1776

2368

2960

<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:

0.361

Hom.:

16009

Bravo

AF:

0.425

Asia WGS

AF:

0.475

AC:

1651

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.11

(source)

DANN

Benign

0.53

PhyloP100

-1.6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over