Genetic Variant NM_001983.4:c.354T>C (chr19-45420395-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_001983.4(ERCC1):c.354T>C(p.Asn118Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,611,696 control chromosomes in the GnomAD database, including 163,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 26981 hom., cov: 31)

Exomes 𝑓: 0.42 ( 136082 hom. )

Consequence

ERCC1
NM_001983.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.629

Publications

589 publications found

Variant links:

Genes affected

ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

ERCC1 Gene-Disease associations (from GenCC):

cerebrooculofacioskeletal syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
Cockayne syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ERCC1 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=-0.83).

BP6

Variant 19-45420395-A-G is Benign according to our data. Variant chr19-45420395-A-G is described in ClinVar as Benign. ClinVar VariationId is 225945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.629 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001983.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC1	NM_001983.4	MANE Select	c.354T>C	p.Asn118Asn	synonymous	Exon 4 of 10	NP_001974.1
ERCC1	NM_001369408.1		c.354T>C	p.Asn118Asn	synonymous	Exon 4 of 9	NP_001356337.1
ERCC1	NM_001369409.1		c.354T>C	p.Asn118Asn	synonymous	Exon 4 of 9	NP_001356338.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC1	ENST00000300853.8	TSL:1 MANE Select	c.354T>C	p.Asn118Asn	synonymous	Exon 4 of 10	ENSP00000300853.3
ERCC1	ENST00000013807.9	TSL:1	c.354T>C	p.Asn118Asn	synonymous	Exon 3 of 8	ENSP00000013807.4
ERCC1	ENST00000340192.11	TSL:1	c.354T>C	p.Asn118Asn	synonymous	Exon 4 of 9	ENSP00000345203.6

Frequencies

GnomAD3 genomes

AF:

0.552

AC:

83875

AN:

151840

Hom.:

26919

Cov.:

show subpopulations

Gnomad AFR

AF:

0.875

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.596

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.737

Gnomad SAS

AF:

0.544

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.436

Gnomad NFE

AF:

0.373

Gnomad OTH

AF:

0.518

GnomAD2 exomes

AF:

0.501

AC:

125107

AN:

249686

AF XY:

0.485

show subpopulations

Gnomad AFR exome

AF:

0.890

Gnomad AMR exome

AF:

0.705

Gnomad ASJ exome

AF:

0.415

Gnomad EAS exome

AF:

0.734

Gnomad FIN exome

AF:

0.363

Gnomad NFE exome

AF:

0.374

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.415

AC:

606069

AN:

1459736

Hom.:

136082

Cov.:

AF XY:

0.416

AC XY:

301953

AN XY:

726166

show subpopulations

African (AFR)

AF:

0.893

AC:

29897

AN:

33464

American (AMR)

AF:

0.689

AC:

30759

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

10564

AN:

26114

East Asian (EAS)

AF:

0.727

AC:

28839

AN:

39680

South Asian (SAS)

AF:

0.528

AC:

45464

AN:

86088

European-Finnish (FIN)

AF:

0.366

AC:

19508

AN:

53304

Middle Eastern (MID)

AF:

0.426

AC:

2455

AN:

5760

European-Non Finnish (NFE)

AF:

0.370

AC:

411309

AN:

1110358

Other (OTH)

AF:

0.452

AC:

27274

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

17854

35709

53563

71418

89272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13416

26832

40248

53664

67080

<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:

0.553

AC:

83997

AN:

151960

Hom.:

26981

Cov.:

AF XY:

0.554

AC XY:

41178

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.875

AC:

36293

AN:

41486

American (AMR)

AF:

0.596

AC:

9089

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1375

AN:

3470

East Asian (EAS)

AF:

0.737

AC:

3796

AN:

5154

South Asian (SAS)

AF:

0.543

AC:

2611

AN:

4806

European-Finnish (FIN)

AF:

0.362

AC:

3831

AN:

10574

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.373

AC:

25340

AN:

67908

Other (OTH)

AF:

0.521

AC:

1098

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1558

3116

4674

6232

7790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.435

Hom.:

80718

Bravo

AF:

0.584

Asia WGS

AF:

0.667

AC:

2322

AN:

3478

EpiCase

AF:

0.381

EpiControl

AF:

0.384

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.010

(source)

DANN

Benign

0.42

PhyloP100

-0.63

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over