16-13943873-A-G

Variant names:

• chr16-13943873-A-G
• rs31870
• NM_005236.3:c.1905-850A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005236.3(ERCC4):​c.1905-850A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.978 in 152,282 control chromosomes in the GnomAD database, including 72,998 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 0.98 (72997 hom., cov: 31)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.399
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.988 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.1905-850A>G		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.1905-850A>G		intron	N/A	ENSP00000310520.7
	ERCC4	ENST00000682617.1		c.2043-850A>G		intron	N/A	ENSP00000507912.1
	ERCC4	ENST00000389138.7	TSL:2	n.1182-850A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148878 AN: 152162 Hom.: 72939 Cov.: 31

Gnomad AFR AF: 0.996

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.801

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.981

Gnomad OTH AF: 0.979

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.978 AC: 148995 AN: 152280 Hom.: 72997 Cov.: 31 AF XY: 0.978 AC XY: 72784 AN XY: 74456

African (AFR) AF: 0.996 AC: 41367 AN: 41542

American (AMR) AF: 0.985 AC: 15077 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 3372 AN: 3472

East Asian (EAS) AF: 0.800 AC: 4144 AN: 5180

South Asian (SAS) AF: 0.978 AC: 4714 AN: 4822

European-Finnish (FIN) AF: 0.977 AC: 10374 AN: 10616

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.981 AC: 66715 AN: 68032

Other (OTH) AF: 0.979 AC: 2065 AN: 2110

Alfa AF: 0.981 Hom.: 10091

Bravo AF: 0.977

Asia WGS AF: 0.923 AC: 3212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.8
DANN	Benign	0.24
PhyloP100		0.40
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: rs31870; hg19: chr16-14037730;