dbSNP rs31304: NDUFS4:p.Gly66Gly (chr5-53646253-A-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002495.4(NDUFS4):c.198A>C(p.Gly66Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,611,208 control chromosomes in the GnomAD database, including 746,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G66G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.96 ( 70618 hom., cov: 29)

Exomes 𝑓: 0.96 ( 675896 hom. )

Consequence

NDUFS4
NM_002495.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.697

Publications

28 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 5-53646253-A-C is Benign according to our data. Variant chr5-53646253-A-C is described in ClinVar as Benign. ClinVar VariationId is 129700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.697 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.967 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	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFS4	NM_002495.4	MANE Select	c.198A>C	p.Gly66Gly	synonymous	Exon 3 of 5	NP_002486.1	A0A0S2Z433
NDUFS4	NM_001318051.2		c.198A>C	p.Gly66Gly	synonymous	Exon 3 of 4	NP_001304980.1
NDUFS4	NR_134473.2		n.394A>C		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.198A>C	p.Gly66Gly	synonymous	Exon 3 of 5	ENSP00000296684.5	O43181
NDUFS4	ENST00000506974.5	TSL:1	n.370A>C		non_coding_transcript_exon	Exon 4 of 6	ENSP00000425967.1	D6RI09
NDUFS4	ENST00000506765.1	TSL:2	c.186A>C	p.Gly62Gly	synonymous	Exon 3 of 4	ENSP00000424570.1	H0Y9M8

Frequencies

GnomAD3 genomes

AF:

0.964

AC:

146398

AN:

151912

Hom.:

70570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.975

Gnomad AMI

AF:

0.968

Gnomad AMR

AF:

0.978

Gnomad ASJ

AF:

0.948

Gnomad EAS

AF:

0.862

Gnomad SAS

AF:

0.947

Gnomad FIN

AF:

0.948

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.966

Gnomad OTH

AF:

0.959

GnomAD2 exomes

AF:

0.955

AC:

238506

AN:

249666

AF XY:

0.954

show subpopulations

Gnomad AFR exome

AF:

0.977

Gnomad AMR exome

AF:

0.984

Gnomad ASJ exome

AF:

0.946

Gnomad EAS exome

AF:

0.853

Gnomad FIN exome

AF:

0.944

Gnomad NFE exome

AF:

0.966

Gnomad OTH exome

AF:

0.953

GnomAD4 exome

AF:

0.962

AC:

1404023

AN:

1459180

Hom.:

675896

Cov.:

AF XY:

0.962

AC XY:

698135

AN XY:

726006

show subpopulations

African (AFR)

AF:

0.975

AC:

32557

AN:

33402

American (AMR)

AF:

0.984

AC:

43927

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.945

AC:

24675

AN:

26102

East Asian (EAS)

AF:

0.852

AC:

33719

AN:

39590

South Asian (SAS)

AF:

0.946

AC:

81450

AN:

86114

European-Finnish (FIN)

AF:

0.942

AC:

50244

AN:

53340

Middle Eastern (MID)

AF:

0.970

AC:

5583

AN:

5758

European-Non Finnish (NFE)

AF:

0.968

AC:

1074150

AN:

1109946

Other (OTH)

AF:

0.958

AC:

57718

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

2604

5208

7813

10417

13021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21594

43188

64782

86376

107970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.964

AC:

146502

AN:

152028

Hom.:

70618

Cov.:

AF XY:

0.962

AC XY:

71475

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.975

AC:

40456

AN:

41486

American (AMR)

AF:

0.978

AC:

14933

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.948

AC:

3285

AN:

3466

East Asian (EAS)

AF:

0.861

AC:

4436

AN:

5152

South Asian (SAS)

AF:

0.947

AC:

4557

AN:

4810

European-Finnish (FIN)

AF:

0.948

AC:

10006

AN:

10560

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.966

AC:

65654

AN:

67980

Other (OTH)

AF:

0.954

AC:

2011

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

250

500

749

999

1249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.967

Hom.:

132534

Bravo

AF:

0.966

Asia WGS

AF:

0.898

AC:

3123

AN:

3478

EpiCase

AF:

0.966

EpiControl

AF:

0.967

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Leigh syndrome (2)

Mitochondrial complex I deficiency, nuclear type 1 (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.20

(source)

DANN

Benign

0.59

PhyloP100

-0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over