rs3136042

Variant names:

• chr16-13920198-C-T
• rs3136042
• NM_005236.3:c.33C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-13920198-C-T
• chr16-13920198-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005236.3(ERCC4):​c.33C>T​(p.Ala11Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,607,076 control chromosomes in the GnomAD database, including 398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (19 hom., cov: 33)
  • Exomes 𝑓: 0.021 (379 hom.)
• Consequence: ERCC4 NM_005236.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.10
• Publications: 12 publications found

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, Genomics England PanelApp
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, 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

LOC105371093 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-13920198-C-T is Benign according to our data. Variant chr16-13920198-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2074/152360) while in subpopulation NFE AF = 0.0229 (1557/68036). AF 95% confidence interval is 0.0219. There are 19 homozygotes in GnomAd4. There are 913 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.33C>T	p.Ala11Ala	synonymous	Exon 1 of 11	NP_005227.1	Q92889-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.33C>T	p.Ala11Ala	synonymous	Exon 1 of 11	ENSP00000310520.7	Q92889-1
	ERCC4	ENST00000575156.5	TSL:1	c.33C>T	p.Ala11Ala	synonymous	Exon 1 of 6	ENSP00000459933.1	Q92889-2
	ERCC4	ENST00000682617.1		c.33C>T	p.Ala11Ala	synonymous	Exon 1 of 12	ENSP00000507912.1	A0A804HKF9

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2068 AN: 152242 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00856

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0128 AC: 3131 AN: 243880 AF XY: 0.0125

Gnomad AFR exome AF: 0.00470

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00758

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00913

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0206 AC: 29950 AN: 1454716 Hom.: 379 Cov.: 35 AF XY: 0.0197 AC XY: 14266 AN XY: 724034

African (AFR) AF: 0.00436 AC: 146 AN: 33474

American (AMR) AF: 0.00445 AC: 199 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00853 AC: 223 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00186 AC: 160 AN: 86248

European-Finnish (FIN) AF: 0.0105 AC: 490 AN: 46542

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5726

European-Non Finnish (NFE) AF: 0.0250 AC: 27789 AN: 1111864

Other (OTH) AF: 0.0155 AC: 936 AN: 60320

GnomAD4 genome AF: 0.0136 AC: 2074 AN: 152360 Hom.: 19 Cov.: 33 AF XY: 0.0123 AC XY: 913 AN XY: 74508

African (AFR) AF: 0.00575 AC: 239 AN: 41586

American (AMR) AF: 0.00823 AC: 126 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00856 AC: 91 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1557 AN: 68036

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.0188 Hom.: 72

Bravo AF: 0.0134

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0179

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Xeroderma pigmentosum, group F (2)
-	-	1	Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.0
DANN	Benign	0.93
PhyloP100		-3.1
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3136042; hg19: chr16-14014055; COSMIC: COSV61313691;