5-60945190-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The ENST00000907122.1(NDUFAF2):c.-66G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,594,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

NDUFAF2
ENST00000907122.1 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -3.35

Publications

0 publications found

Variant links:

Genes affected

NDUFAF2 (HGNC:28086): (NADH:ubiquinone oxidoreductase complex assembly factor 2) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]

NDUFAF2 links:

ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

ERCC8 Gene-Disease associations (from GenCC):

Cockayne syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, G2P, Laboratory for Molecular Medicine, Myriad Women’s Health, PanelApp Australia, Labcorp Genetics (formerly Invitae)
UV-sensitive syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
Cockayne syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
UV-sensitive syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ERCC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000464 (67/1442772) while in subpopulation AMR AF = 0.000482 (20/41488). AF 95% confidence interval is 0.000319. There are 0 homozygotes in GnomAdExome4. There are 39 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000907122.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC8	NM_000082.4	MANE Select	c.-182C>G	upstream_gene	N/A	NP_000073.1	Q13216-1
NDUFAF2	NM_174889.5	MANE Select	c.-66G>C	upstream_gene	N/A	NP_777549.1	A0A0S2Z5U1
ERCC8	NM_001007233.3		c.-574C>G	upstream_gene	N/A	NP_001007234.1	B3KPW7

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
NDUFAF2	ENST00000907122.1	c.-66G>C	5_prime_UTR	Exon 1 of 3	ENSP00000577181.1
NDUFAF2	ENST00000677756.1	n.-66G>C	non_coding_transcript_exon	Exon 1 of 6	ENSP00000503642.1	A0A7I2V3X5
NDUFAF2	ENST00000678452.1	n.-66G>C	non_coding_transcript_exon	Exon 1 of 4	ENSP00000504248.1	A0A7I2V4Z7

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000464

AC:

AN:

1442772

Hom.:

Cov.:

AF XY:

0.0000545

AC XY:

AN XY:

716140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33018

American (AMR)

AF:

0.000482

AC:

AN:

41488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25772

East Asian (EAS)

AF:

0.00

AC:

AN:

38770

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4356

European-Non Finnish (NFE)

AF:

0.0000362

AC:

AN:

1103616

Other (OTH)

AF:

0.000101

AC:

AN:

59596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000592

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.000196

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000718

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leigh syndrome (1)

Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.021

(source)

DANN

Benign

0.44

PhyloP100

-3.3

PromoterAI

-0.073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

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