16-13932150-G-A

Variant names:

• chr16-13932150-G-A
• rs254942
• NM_005236.3:c.974-7G>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.974-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 1,612,468 control chromosomes in the GnomAD database, including 769,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72873 hom., cov: 32)
  • Exomes 𝑓: 0.98 (696379 hom.)
• Consequence: ERCC4 NM_005236.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001776
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.96
• Publications: 20 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: ClinGen, G2P, Genomics England PanelApp
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000262732 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-13932150-G-A is Benign according to our data. Variant chr16-13932150-G-A is described in ClinVar as Benign. ClinVar VariationId is 259686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.987 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.974-7G>A		splice_region intron	N/A	NP_005227.1	Q92889-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.974-7G>A		splice_region intron	N/A	ENSP00000310520.7	Q92889-1
	ERCC4	ENST00000575156.5	TSL:1	c.974-7G>A		splice_region intron	N/A	ENSP00000459933.1	Q92889-2
	ERCC4	ENST00000682617.1		c.1112-7G>A		splice_region intron	N/A	ENSP00000507912.1	A0A804HKF9

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148762 AN: 152224 Hom.: 72814 Cov.: 32

Gnomad AFR AF: 0.995

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.980

Gnomad OTH AF: 0.979

GnomAD2 exomes AF: 0.966 AC: 242632 AN: 251260 AF XY: 0.967

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.976

Gnomad ASJ exome AF: 0.967

Gnomad EAS exome AF: 0.787

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.981

Gnomad OTH exome AF: 0.976

GnomAD4 exome AF: 0.976 AC: 1425233 AN: 1460126 Hom.: 696379 Cov.: 38 AF XY: 0.976 AC XY: 709305 AN XY: 726558

African (AFR) AF: 0.997 AC: 33337 AN: 33448

American (AMR) AF: 0.977 AC: 43695 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 25285 AN: 26126

East Asian (EAS) AF: 0.793 AC: 31471 AN: 39676

South Asian (SAS) AF: 0.978 AC: 84354 AN: 86220

European-Finnish (FIN) AF: 0.979 AC: 52127 AN: 53272

Middle Eastern (MID) AF: 0.978 AC: 5576 AN: 5704

European-Non Finnish (NFE) AF: 0.982 AC: 1090824 AN: 1110600

Other (OTH) AF: 0.970 AC: 58564 AN: 60356

GnomAD4 genome AF: 0.977 AC: 148879 AN: 152342 Hom.: 72873 Cov.: 32 AF XY: 0.976 AC XY: 72729 AN XY: 74498

African (AFR) AF: 0.995 AC: 41386 AN: 41578

American (AMR) AF: 0.985 AC: 15073 AN: 15308

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

East Asian (EAS) AF: 0.777 AC: 4018 AN: 5174

South Asian (SAS) AF: 0.977 AC: 4718 AN: 4828

European-Finnish (FIN) AF: 0.977 AC: 10378 AN: 10620

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.980 AC: 66699 AN: 68042

Other (OTH) AF: 0.979 AC: 2069 AN: 2114

Alfa AF: 0.981 Hom.: 132843

Bravo AF: 0.976

Asia WGS AF: 0.910 AC: 3165 AN: 3478

EpiCase AF: 0.980

EpiControl AF: 0.981

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Xeroderma pigmentosum, group F (3)
-	-	2	not specified (2)
-	-	1	Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (1)
-	-	1	Fanconi anemia complementation group Q (1)
-	-	1	XFE progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.010
DANN	Benign	0.81
PhyloP100		-5.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0020
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: rs254942; hg19: chr16-14026007;