rs1799798

Variant names:

• chr16-13920421-G-A
• rs1799798
• NM_005236.3:c.207+49G>A

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+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 1,488,370 control chromosomes in the GnomAD database, including 8,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (726 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8050 hom.)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.831
• Publications: 15 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=-0.8).
• BP6: Variant 16-13920421-G-A is Benign according to our data. Variant chr16-13920421-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.213 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+49G>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+49G>A		intron	N/A	ENSP00000310520.7
	ERCC4	ENST00000575156.5	TSL:1	c.207+49G>A		intron	N/A	ENSP00000459933.1
	ERCC4	ENST00000683277.1		n.243G>A		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 12248 AN: 152184 Hom.: 725 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.0757

GnomAD2 exomes AF: 0.125 AC: 17108 AN: 137318 AF XY: 0.127

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0902

Gnomad OTH exome AF: 0.0966

GnomAD4 exome AF: 0.100 AC: 133610 AN: 1336068 Hom.: 8050 Cov.: 23 AF XY: 0.103 AC XY: 68455 AN XY: 662346

African (AFR) AF: 0.0148 AC: 456 AN: 30708

American (AMR) AF: 0.182 AC: 6484 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 733 AN: 24880

East Asian (EAS) AF: 0.135 AC: 4811 AN: 35572

South Asian (SAS) AF: 0.213 AC: 16759 AN: 78510

European-Finnish (FIN) AF: 0.111 AC: 3784 AN: 34232

Middle Eastern (MID) AF: 0.0431 AC: 172 AN: 3994

European-Non Finnish (NFE) AF: 0.0919 AC: 95253 AN: 1036184

Other (OTH) AF: 0.0916 AC: 5158 AN: 56280

GnomAD4 genome AF: 0.0804 AC: 12248 AN: 152302 Hom.: 726 Cov.: 32 AF XY: 0.0858 AC XY: 6390 AN XY: 74476

African (AFR) AF: 0.0197 AC: 818 AN: 41590

American (AMR) AF: 0.138 AC: 2112 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.116 AC: 602 AN: 5172

South Asian (SAS) AF: 0.224 AC: 1078 AN: 4818

European-Finnish (FIN) AF: 0.109 AC: 1154 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0905 AC: 6156 AN: 68020

Other (OTH) AF: 0.0773 AC: 163 AN: 2108

Alfa AF: 0.0796 Hom.: 148

Bravo AF: 0.0755

Asia WGS AF: 0.178 AC: 615 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.5
DANN	Benign	0.83
PhyloP100		0.83
PromoterAI		-0.14	Neutral
Mutation Taster		=100/0	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: rs1799798; hg19: chr16-14014278;