Genetic Variant NDUFS4:c.350+3023T>C (chr5-53649428-T-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.350+3023T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,074 control chromosomes in the GnomAD database, including 5,911 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 0.26 ( 5911 hom., cov: 32)

Consequence

NDUFS4
NM_002495.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.489

Publications

9 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=-0.92).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.342 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.350+3023T>C	intron	N/A	NP_002486.1	A0A0S2Z433
NDUFS4	NM_001318051.2		c.350+3023T>C	intron	N/A	NP_001304980.1
NDUFS4	NR_134473.2		n.546+3023T>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.350+3023T>C	intron	N/A	ENSP00000296684.5	O43181
NDUFS4	ENST00000506974.5	TSL:1	n.*126+3023T>C	intron	N/A	ENSP00000425967.1	D6RI09
NDUFS4	ENST00000856911.1		c.350-33690T>C	intron	N/A	ENSP00000526970.1

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

39943

AN:

151956

Hom.:

5910

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.349

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.339

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.315

Gnomad OTH

AF:

0.252

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

GnomAD4 genome

AF:

0.263

AC:

39955

AN:

152074

Hom.:

5911

Cov.:

AF XY:

0.265

AC XY:

19724

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.139

AC:

5770

AN:

41514

American (AMR)

AF:

0.349

AC:

5333

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1032

AN:

3472

East Asian (EAS)

AF:

0.130

AC:

673

AN:

5176

South Asian (SAS)

AF:

0.296

AC:

1424

AN:

4812

European-Finnish (FIN)

AF:

0.339

AC:

3584

AN:

10558

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.315

AC:

21379

AN:

67966

Other (OTH)

AF:

0.249

AC:

523

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1458

2915

4373

5830

7288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<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:

0.297

Hom.:

19805

Bravo

AF:

0.258

Asia WGS

AF:

0.212

AC:

743

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

3.8

(source)

DANN

Benign

0.56

PhyloP100

0.49

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