rs3136146

Variant names:

• chr16-13934522-G-A
• rs3136146
• NM_005236.3:c.1213+220G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-13934522-G-A
• chr16-13934522-G-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.1213+220G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 510,630 control chromosomes in the GnomAD database, including 6,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (5054 hom., cov: 32)
  • Exomes 𝑓: 0.068 (1923 hom.)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.193
• Publications: 8 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

ENSG00000262732 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-13934522-G-A is Benign according to our data. Variant chr16-13934522-G-A is described in ClinVar as Benign. ClinVar VariationId is 1178890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.1213+220G>A		intron_variant	Intron 7 of 10	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.1351+220G>A		intron_variant	Intron 8 of 11		XP_011520726.1
ERCC4	XM_047433774.1	c.424+220G>A		intron_variant	Intron 4 of 7		XP_047289730.1
ERCC4	XM_011522427.2	c.-138+220G>A		intron_variant	Intron 2 of 5		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.1213+220G>A		intron_variant	Intron 7 of 10	1	NM_005236.3	ENSP00000310520.7

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27026 AN: 151964 Hom.: 5028 Cov.: 32

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0949

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0739

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0607

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.0683 AC: 24505 AN: 358548 Hom.: 1923 Cov.: 0 AF XY: 0.0639 AC XY: 12217 AN XY: 191234

African (AFR) AF: 0.475 AC: 4960 AN: 10434

American (AMR) AF: 0.0974 AC: 1351 AN: 13876

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 1070 AN: 11220

East Asian (EAS) AF: 0.000255 AC: 6 AN: 23556

South Asian (SAS) AF: 0.0264 AC: 1102 AN: 41682

European-Finnish (FIN) AF: 0.0705 AC: 1285 AN: 18226

Middle Eastern (MID) AF: 0.0894 AC: 139 AN: 1554

European-Non Finnish (NFE) AF: 0.0590 AC: 12822 AN: 217290

Other (OTH) AF: 0.0855 AC: 1770 AN: 20710

GnomAD4 genome AF: 0.178 AC: 27093 AN: 152082 Hom.: 5054 Cov.: 32 AF XY: 0.174 AC XY: 12904 AN XY: 74344

African (AFR) AF: 0.472 AC: 19556 AN: 41432

American (AMR) AF: 0.113 AC: 1732 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 329 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0268 AC: 129 AN: 4822

European-Finnish (FIN) AF: 0.0739 AC: 781 AN: 10570

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0607 AC: 4130 AN: 68004

Other (OTH) AF: 0.137 AC: 290 AN: 2112

Alfa AF: 0.0859 Hom.: 2082

Bravo AF: 0.195

Asia WGS AF: 0.0430 AC: 149 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.64
DANN	Benign	0.47
PhyloP100		-0.19
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: rs3136146; hg19: chr16-14028379;