dbSNP rs4150524: ERCC3:c.*106T>C (chr2-127257490-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000122.2(ERCC3):c.*106T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,454,330 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 11 hom. )

Consequence

ERCC3
NM_000122.2 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0150

Publications

1 publications found

Variant links:

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 Gene-Disease associations (from GenCC):

trichothiodystrophy 2, photosensitive
Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
xeroderma pigmentosum group B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
trichothiodystrophy 1, photosensitive
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
trichothiodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum-Cockayne syndrome complex
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ERCC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-127257490-A-G is Benign according to our data. Variant chr2-127257490-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 331071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00839 (1278/152330) while in subpopulation AFR AF = 0.0293 (1218/41566). AF 95% confidence interval is 0.0279. There are 20 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000122.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC3	NM_000122.2	MANE Select	c.*106T>C	3_prime_UTR	Exon 15 of 15	NP_000113.1	P19447
ERCC3	NM_001303416.2		c.*106T>C	3_prime_UTR	Exon 15 of 15	NP_001290345.1
ERCC3	NM_001303418.2		c.*106T>C	3_prime_UTR	Exon 15 of 15	NP_001290347.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERCC3	ENST00000285398.7	TSL:1 MANE Select	c.*106T>C		3_prime_UTR	Exon 15 of 15	ENSP00000285398.2	P19447
ERCC3	ENST00000647496.1		c.506T>C	p.Val169Ala	missense	Exon 5 of 5	ENSP00000496038.1	A0A2R8Y762
ERCC3	ENST00000647169.1		c.*106T>C		3_prime_UTR	Exon 16 of 16	ENSP00000495619.1	A0A2R8Y6W8

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1266

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00670

GnomAD4 exome

AF:

0.000912

AC:

1188

AN:

1302000

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

520

AN XY:

656220

show subpopulations

African (AFR)

AF:

0.0303

AC:

917

AN:

30302

American (AMR)

AF:

0.00180

AC:

AN:

44468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38966

South Asian (SAS)

AF:

0.0000729

AC:

AN:

82284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53090

Middle Eastern (MID)

AF:

0.00182

AC:

AN:

3854

European-Non Finnish (NFE)

AF:

0.0000506

AC:

AN:

968878

Other (OTH)

AF:

0.00233

AC:

128

AN:

54984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00839

AC:

1278

AN:

152330

Hom.:

Cov.:

AF XY:

0.00789

AC XY:

588

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0293

AC:

1218

AN:

41566

American (AMR)

AF:

0.00248

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00580

Hom.:

Bravo

AF:

0.00936

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Xeroderma pigmentosum group B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.62

(source)

DANN

Benign

0.39

PhyloP100

-0.015

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(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