Genetic Variant NM_002495.4:c.312A>G (chr5-53646367-A-G) – 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.312A>G(p.Arg104Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,613,250 control chromosomes in the GnomAD database, including 479,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 47554 hom., cov: 31)

Exomes 𝑓: 0.77 ( 432296 hom. )

Consequence

NDUFS4
NM_002495.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.713

Publications

35 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=-0.53).

BP6

Variant 5-53646367-A-G is Benign according to our data. Variant chr5-53646367-A-G is described in ClinVar as Benign. ClinVar VariationId is 129701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.713 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 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.312A>G	p.Arg104Arg	synonymous	Exon 3 of 5	NP_002486.1	A0A0S2Z433
NDUFS4	NM_001318051.2		c.312A>G	p.Arg104Arg	synonymous	Exon 3 of 4	NP_001304980.1
NDUFS4	NR_134473.2		n.508A>G		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.312A>G	p.Arg104Arg	synonymous	Exon 3 of 5	ENSP00000296684.5	O43181
NDUFS4	ENST00000506974.5	TSL:1	n.*88A>G		non_coding_transcript_exon	Exon 4 of 6	ENSP00000425967.1	D6RI09
NDUFS4	ENST00000506974.5	TSL:1	n.*88A>G		3_prime_UTR	Exon 4 of 6	ENSP00000425967.1	D6RI09

Frequencies

GnomAD3 genomes

AF:

0.789

AC:

119917

AN:

151958

Hom.:

47509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.852

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.806

Gnomad ASJ

AF:

0.735

Gnomad EAS

AF:

0.769

Gnomad SAS

AF:

0.776

Gnomad FIN

AF:

0.754

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.761

Gnomad OTH

AF:

0.772

GnomAD2 exomes

AF:

0.775

AC:

194783

AN:

251396

AF XY:

0.774

show subpopulations

Gnomad AFR exome

AF:

0.856

Gnomad AMR exome

AF:

0.804

Gnomad ASJ exome

AF:

0.738

Gnomad EAS exome

AF:

0.773

Gnomad FIN exome

AF:

0.754

Gnomad NFE exome

AF:

0.762

Gnomad OTH exome

AF:

0.764

GnomAD4 exome

AF:

0.769

AC:

1122971

AN:

1461174

Hom.:

432296

Cov.:

AF XY:

0.768

AC XY:

558472

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.856

AC:

28643

AN:

33466

American (AMR)

AF:

0.805

AC:

35991

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.734

AC:

19181

AN:

26126

East Asian (EAS)

AF:

0.732

AC:

29054

AN:

39666

South Asian (SAS)

AF:

0.778

AC:

67051

AN:

86238

European-Finnish (FIN)

AF:

0.753

AC:

40199

AN:

53406

Middle Eastern (MID)

AF:

0.773

AC:

4453

AN:

5758

European-Non Finnish (NFE)

AF:

0.766

AC:

851542

AN:

1111442

Other (OTH)

AF:

0.776

AC:

46857

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

13446

26892

40338

53784

67230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20496

40992

61488

81984

102480

<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:

0.789

AC:

120019

AN:

152076

Hom.:

47554

Cov.:

AF XY:

0.790

AC XY:

58678

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.852

AC:

35359

AN:

41506

American (AMR)

AF:

0.806

AC:

12304

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.735

AC:

2553

AN:

3472

East Asian (EAS)

AF:

0.768

AC:

3961

AN:

5156

South Asian (SAS)

AF:

0.775

AC:

3732

AN:

4816

European-Finnish (FIN)

AF:

0.754

AC:

7969

AN:

10562

Middle Eastern (MID)

AF:

0.816

AC:

240

AN:

294

European-Non Finnish (NFE)

AF:

0.761

AC:

51718

AN:

67972

Other (OTH)

AF:

0.769

AC:

1626

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1287

2574

3862

5149

6436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<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:

0.771

Hom.:

91191

Bravo

AF:

0.794

Asia WGS

AF:

0.777

AC:

2702

AN:

3478

EpiCase

AF:

0.757

EpiControl

AF:

0.763

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Mitochondrial complex I deficiency, nuclear type 1 (2)

Leigh syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.2

(source)

DANN

Benign

0.62

PhyloP100

0.71

Mutation Taster

=89/11

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over