rs762521

Variant names:

• chr16-13920383-G-A
• rs762521
• NM_005236.3:c.207+11G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-13920383-G-A
• chr16-13920383-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005236.3(ERCC4):​c.207+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,554,340 control chromosomes in the GnomAD database, including 55,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4387 hom., cov: 33)
  • Exomes 𝑓: 0.27 (51362 hom.)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.67
• 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: Genomics England PanelApp, G2P, ClinGen
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-13920383-G-A is Benign according to our data. Variant chr16-13920383-G-A is described in ClinVar as Benign. ClinVar VariationId is 259683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	NM_005236.3	MANE Select	c.207+11G>A		intron	N/A	NP_005227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.207+11G>A		intron	N/A	ENSP00000310520.7
	ERCC4	ENST00000575156.5	TSL:1	c.207+11G>A		intron	N/A	ENSP00000459933.1
	ERCC4	ENST00000683277.1		n.205G>A		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35270 AN: 152074 Hom.: 4383 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.250 AC: 40797 AN: 162972 AF XY: 0.257

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.296

Gnomad EAS exome AF: 0.263

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.268 AC: 375739 AN: 1402148 Hom.: 51362 Cov.: 34 AF XY: 0.269 AC XY: 186949 AN XY: 694438

African (AFR) AF: 0.171 AC: 5512 AN: 32272

American (AMR) AF: 0.149 AC: 5727 AN: 38358

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7406 AN: 25410

East Asian (EAS) AF: 0.249 AC: 9215 AN: 36954

South Asian (SAS) AF: 0.251 AC: 20504 AN: 81620

European-Finnish (FIN) AF: 0.229 AC: 8288 AN: 36200

Middle Eastern (MID) AF: 0.328 AC: 1435 AN: 4378

European-Non Finnish (NFE) AF: 0.278 AC: 302366 AN: 1088506

Other (OTH) AF: 0.262 AC: 15286 AN: 58450

GnomAD4 genome AF: 0.232 AC: 35291 AN: 152192 Hom.: 4387 Cov.: 33 AF XY: 0.229 AC XY: 17063 AN XY: 74402

African (AFR) AF: 0.173 AC: 7182 AN: 41548

American (AMR) AF: 0.182 AC: 2789 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 982 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1349 AN: 5164

South Asian (SAS) AF: 0.245 AC: 1183 AN: 4822

European-Finnish (FIN) AF: 0.229 AC: 2429 AN: 10602

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18457 AN: 67976

Other (OTH) AF: 0.263 AC: 555 AN: 2108

Alfa AF: 0.266 Hom.: 985

Bravo AF: 0.226

Asia WGS AF: 0.278 AC: 967 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		2.7
PromoterAI		-0.11	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762521; hg19: chr16-14014240; COSMIC: COSV61311241; COSMIC: COSV61311241;