Genetic Variant NM_005236.3:c.1905-406G>A (chr16-13944317-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005236.3(ERCC4):c.1905-406G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 151,760 control chromosomes in the GnomAD database, including 14,525 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 0.41 ( 14525 hom., cov: 32)

Consequence

ERCC4
NM_005236.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.95

Publications

23 publications found

Variant links:

Genes affected

ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

ERCC4 Gene-Disease associations (from GenCC):

xeroderma pigmentosum group F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Genomics England PanelApp
Fanconi anemia complementation group Q
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
XFE progeroid syndrome
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
Fanconi anemia
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

ERCC4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005236.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005236.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	NM_005236.3	MANE Select	c.1905-406G>A		intron	N/A	NP_005227.1	Q92889-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.1905-406G>A	intron	N/A	ENSP00000310520.7	Q92889-1
ERCC4	ENST00000682617.1		c.2043-406G>A	intron	N/A	ENSP00000507912.1	A0A804HKF9
ERCC4	ENST00000389138.7	TSL:2	n.1182-406G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.412

AC:

62493

AN:

151642

Hom.:

14483

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.429

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.248

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.311

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.343

Gnomad OTH

AF:

0.411

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.412

AC:

62588

AN:

151760

Hom.:

14525

Cov.:

AF XY:

0.406

AC XY:

30078

AN XY:

74148

show subpopulations

African (AFR)

AF:

0.631

AC:

26119

AN:

41402

American (AMR)

AF:

0.302

AC:

4612

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

1353

AN:

3468

East Asian (EAS)

AF:

0.248

AC:

1278

AN:

5158

South Asian (SAS)

AF:

0.273

AC:

1309

AN:

4794

European-Finnish (FIN)

AF:

0.311

AC:

3247

AN:

10452

Middle Eastern (MID)

AF:

0.428

AC:

125

AN:

292

European-Non Finnish (NFE)

AF:

0.343

AC:

23287

AN:

67912

Other (OTH)

AF:

0.412

AC:

867

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1756

3512

5268

7024

8780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.362

Hom.:

36680

Bravo

AF:

0.423

Asia WGS

AF:

0.320

AC:

1114

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.17

(source)

DANN

Benign

0.45

PhyloP100

-2.0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over