rs4147707

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_005006.7(NDUFS1):c.-47C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 559,318 control chromosomes in the GnomAD database, including 47,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14579 hom., cov: 33)

Exomes 𝑓: 0.40 ( 32872 hom. )

Consequence

NDUFS1
NM_005006.7 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.346

Publications

10 publications found

Variant links:

Genes affected

NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

NDUFS1 links:

EEF1B2 (HGNC:3208): (eukaryotic translation elongation factor 1 beta 2) This gene encodes a translation elongation factor. The protein is a guanine nucleotide exchange factor involved in the transfer of aminoacylated tRNAs to the ribosome. Alternative splicing results in three transcript variants which differ only in the 5' UTR. [provided by RefSeq, Jul 2008]

EEF1B2 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

EEF1B2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-206159383-G-C is Benign according to our data. Variant chr2-206159383-G-C is described in ClinVar as Benign. ClinVar VariationId is 333790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS1	NM_005006.7 link	c.-47C>G		5_prime_UTR_variant	Exon 1 of 19	ENST00000233190.11	NP_004997.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11 link	c.-47C>G		5_prime_UTR_variant	Exon 1 of 19	1	NM_005006.7	ENSP00000233190.5

Frequencies

GnomAD3 genomes

AF:

0.432

AC:

65611

AN:

151964

Hom.:

14557

Cov.:

show subpopulations

Gnomad AFR

AF:

0.499

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.508

Gnomad EAS

AF:

0.226

Gnomad SAS

AF:

0.276

Gnomad FIN

AF:

0.447

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.402

Gnomad OTH

AF:

0.453

GnomAD4 exome

AF:

0.396

AC:

161148

AN:

407236

Hom.:

32872

Cov.:

AF XY:

0.390

AC XY:

83312

AN XY:

213414

show subpopulations

African (AFR)

AF:

0.509

AC:

5911

AN:

11624

American (AMR)

AF:

0.483

AC:

8397

AN:

17382

Ashkenazi Jewish (ASJ)

AF:

0.497

AC:

6233

AN:

12542

East Asian (EAS)

AF:

0.208

AC:

6087

AN:

29222

South Asian (SAS)

AF:

0.298

AC:

11368

AN:

38170

European-Finnish (FIN)

AF:

0.441

AC:

12043

AN:

27294

Middle Eastern (MID)

AF:

0.509

AC:

914

AN:

1796

European-Non Finnish (NFE)

AF:

0.408

AC:

100055

AN:

245192

Other (OTH)

AF:

0.422

AC:

10140

AN:

24014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

4367

8734

13101

17468

21835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

516

1032

1548

2064

2580

<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:

0.432

AC:

65684

AN:

152082

Hom.:

14579

Cov.:

AF XY:

0.431

AC XY:

32017

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.499

AC:

20704

AN:

41472

American (AMR)

AF:

0.481

AC:

7350

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.508

AC:

1760

AN:

3466

East Asian (EAS)

AF:

0.225

AC:

1166

AN:

5172

South Asian (SAS)

AF:

0.277

AC:

1332

AN:

4814

European-Finnish (FIN)

AF:

0.447

AC:

4729

AN:

10576

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.402

AC:

27308

AN:

67988

Other (OTH)

AF:

0.449

AC:

950

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1962

3925

5887

7850

9812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<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:

0.418

Hom.:

1874

Bravo

AF:

0.439

Asia WGS

AF:

0.261

AC:

907

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leigh syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Mitochondrial complex I deficiency, nuclear type 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.9

(source)

DANN

Benign

0.60

PhyloP100

0.35

PromoterAI

0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=300/0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over