dbSNP rs4235483: ERCC8:c.844-1309G>A (chr5-60892395-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000082.4(ERCC8):c.844-1309G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 542,060 control chromosomes in the GnomAD database, including 36,133 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 0.37 ( 10697 hom., cov: 31)

Exomes 𝑓: 0.35 ( 25436 hom. )

Consequence

ERCC8
NM_000082.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.96

Publications

16 publications found

Variant links:

Genes affected

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 links:

GNL3LP1 (HGNC:25733): (G protein nucleolar 3 like pseudogene 1)

GNL3LP1 links:

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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=-0.61).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000082.4. 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.844-1309G>A	intron	N/A	NP_000073.1	Q13216-1
ERCC8	NM_001007233.3		c.670-1309G>A	intron	N/A	NP_001007234.1	B3KPW7
ERCC8	NM_001290285.2		c.385-1309G>A	intron	N/A	NP_001277214.1	B4DGZ9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC8	ENST00000676185.1	MANE Select	c.844-1309G>A	intron	N/A	ENSP00000501614.1	Q13216-1
ERCC8	ENST00000265038.10	TSL:1	c.901-1309G>A	intron	N/A	ENSP00000265038.6	A0A7I2PE23
ERCC8	ENST00000891473.1		c.856-1309G>A	intron	N/A	ENSP00000561532.1

Frequencies

GnomAD3 genomes

AF:

0.367

AC:

55784

AN:

151824

Hom.:

10681

Cov.:

show subpopulations

Gnomad AFR

AF:

0.385

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.317

Gnomad ASJ

AF:

0.429

Gnomad EAS

AF:

0.0569

Gnomad SAS

AF:

0.329

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.394

Gnomad OTH

AF:

0.383

GnomAD4 exome

AF:

0.350

AC:

136398

AN:

390118

Hom.:

25436

Cov.:

AF XY:

0.352

AC XY:

77383

AN XY:

220008

show subpopulations

African (AFR)

AF:

0.377

AC:

4135

AN:

10968

American (AMR)

AF:

0.236

AC:

8327

AN:

35292

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

4501

AN:

11020

East Asian (EAS)

AF:

0.0538

AC:

869

AN:

16154

South Asian (SAS)

AF:

0.327

AC:

20560

AN:

62916

European-Finnish (FIN)

AF:

0.377

AC:

11953

AN:

31720

Middle Eastern (MID)

AF:

0.432

AC:

1248

AN:

2888

European-Non Finnish (NFE)

AF:

0.388

AC:

78086

AN:

201034

Other (OTH)

AF:

0.371

AC:

6719

AN:

18126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

3653

7306

10959

14612

18265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.367

AC:

55831

AN:

151942

Hom.:

10697

Cov.:

AF XY:

0.364

AC XY:

27040

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.385

AC:

15942

AN:

41420

American (AMR)

AF:

0.318

AC:

4850

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.429

AC:

1488

AN:

3472

East Asian (EAS)

AF:

0.0570

AC:

295

AN:

5174

South Asian (SAS)

AF:

0.329

AC:

1584

AN:

4816

European-Finnish (FIN)

AF:

0.363

AC:

3825

AN:

10546

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.394

AC:

26772

AN:

67928

Other (OTH)

AF:

0.379

AC:

799

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1771

3543

5314

7086

8857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.379

Hom.:

3601

Bravo

AF:

0.363

Asia WGS

AF:

0.183

AC:

636

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.9

(source)

DANN

Benign

0.51

PhyloP100

3.0

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