16-13949318-C-G

Variant names:

• chr16-13949318-C-G
• rs2276466
• NM_005236.3:c.*971C>G

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.*971C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 233,622 control chromosomes in the GnomAD database, including 8,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4938 hom., cov: 32)
  • Exomes 𝑓: 0.28 (3179 hom.)
• Consequence: ERCC4 NM_005236.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.14
• Publications: 43 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-13949318-C-G is Benign according to our data. Variant chr16-13949318-C-G is described in ClinVar as Benign. ClinVar VariationId is 317841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 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.*971C>G		3_prime_UTR	Exon 11 of 11	NP_005227.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.*971C>G		3_prime_UTR	Exon 11 of 11	ENSP00000310520.7
	ERCC4	ENST00000682617.1		c.*971C>G		3_prime_UTR	Exon 12 of 12	ENSP00000507912.1
	ERCC4	ENST00000683962.1		n.*3416C>G		non_coding_transcript_exon	Exon 12 of 12	ENSP00000506854.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37501 AN: 151952 Hom.: 4929 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.277 AC: 22614 AN: 81552 Hom.: 3179 Cov.: 0 AF XY: 0.281 AC XY: 10556 AN XY: 37528

African (AFR) AF: 0.163 AC: 637 AN: 3898

American (AMR) AF: 0.267 AC: 669 AN: 2506

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1608 AN: 5138

East Asian (EAS) AF: 0.230 AC: 2651 AN: 11506

South Asian (SAS) AF: 0.308 AC: 218 AN: 708

European-Finnish (FIN) AF: 0.185 AC: 37 AN: 200

Middle Eastern (MID) AF: 0.352 AC: 174 AN: 494

European-Non Finnish (NFE) AF: 0.292 AC: 14696 AN: 50314

Other (OTH) AF: 0.283 AC: 1924 AN: 6788

GnomAD4 genome AF: 0.247 AC: 37539 AN: 152070 Hom.: 4938 Cov.: 32 AF XY: 0.246 AC XY: 18254 AN XY: 74336

African (AFR) AF: 0.168 AC: 6968 AN: 41474

American (AMR) AF: 0.248 AC: 3789 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1054 AN: 3466

East Asian (EAS) AF: 0.240 AC: 1242 AN: 5178

South Asian (SAS) AF: 0.302 AC: 1456 AN: 4816

European-Finnish (FIN) AF: 0.241 AC: 2546 AN: 10552

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19475 AN: 67992

Other (OTH) AF: 0.287 AC: 605 AN: 2106

Alfa AF: 0.153 Hom.: 336

Bravo AF: 0.244

Asia WGS AF: 0.295 AC: 1028 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Xeroderma pigmentosum, group F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.73
DANN	Benign	0.51
PhyloP100		-2.1
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: rs2276466; hg19: chr16-14043175;