16-13944688-T-C

Variant names:

• chr16-13944688-T-C
• rs1799799
• NM_005236.3:c.1905-35T>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.1905-35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,353,222 control chromosomes in the GnomAD database, including 79,505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10291 hom., cov: 33)
  • Exomes 𝑓: 0.33 (69214 hom.)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.482
• Publications: 14 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=-0.88).
• BP6: Variant 16-13944688-T-C is Benign according to our data. Variant chr16-13944688-T-C is described in ClinVar as Benign. ClinVar VariationId is 1255392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 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.1905-35T>C		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.1905-35T>C		intron	N/A	ENSP00000310520.7
	ERCC4	ENST00000682617.1		c.2043-35T>C		intron	N/A	ENSP00000507912.1
	ERCC4	ENST00000389138.7	TSL:2	n.1182-35T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54716 AN: 151916 Hom.: 10256 Cov.: 33

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.317 AC: 79088 AN: 249690 AF XY: 0.317

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.334 AC: 401543 AN: 1201188 Hom.: 69214 Cov.: 16 AF XY: 0.334 AC XY: 203688 AN XY: 610612

African (AFR) AF: 0.455 AC: 12923 AN: 28408

American (AMR) AF: 0.228 AC: 10084 AN: 44298

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 9567 AN: 24442

East Asian (EAS) AF: 0.232 AC: 8938 AN: 38532

South Asian (SAS) AF: 0.278 AC: 22494 AN: 80872

European-Finnish (FIN) AF: 0.305 AC: 16224 AN: 53202

Middle Eastern (MID) AF: 0.423 AC: 2218 AN: 5242

European-Non Finnish (NFE) AF: 0.345 AC: 301551 AN: 874428

Other (OTH) AF: 0.339 AC: 17544 AN: 51764

GnomAD4 genome AF: 0.360 AC: 54796 AN: 152034 Hom.: 10291 Cov.: 33 AF XY: 0.356 AC XY: 26435 AN XY: 74320

African (AFR) AF: 0.454 AC: 18828 AN: 41454

American (AMR) AF: 0.282 AC: 4305 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1319 AN: 3466

East Asian (EAS) AF: 0.247 AC: 1274 AN: 5168

South Asian (SAS) AF: 0.271 AC: 1308 AN: 4826

European-Finnish (FIN) AF: 0.308 AC: 3257 AN: 10570

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23214 AN: 67952

Other (OTH) AF: 0.371 AC: 782 AN: 2108

Alfa AF: 0.363 Hom.: 1879

Bravo AF: 0.364

Asia WGS AF: 0.308 AC: 1074 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fanconi anemia complementation group Q (1)
-	-	1	Xeroderma pigmentosum, group F (1)
-	-	1	XFE progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.91
DANN	Benign	0.47
PhyloP100		-0.48
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: rs1799799; hg19: chr16-14038545; COSMIC: COSV61310522;