rs4150407

Variant names:

• chr2-127292055-T-C
• rs4150407
• NM_000122.2:c.471+555A>G

Variant summary

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

The NM_000122.2(ERCC3):​c.471+555A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 183,616 control chromosomes in the GnomAD database, including 20,393 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 0.47 (17020 hom., cov: 32)
  • Exomes 𝑓: 0.43 (3373 hom.)
• Consequence: ERCC3 NM_000122.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.553
• Publications: 19 publications found

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 Gene-Disease associations (from GenCC):

• trichothiodystrophy 2, photosensitive

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• xeroderma pigmentosum group B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• trichothiodystrophy

  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
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC3	NM_000122.2	c.471+555A>G		intron_variant	Intron 3 of 14	ENST00000285398.7	NP_000113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC3	ENST00000285398.7	c.471+555A>G		intron_variant	Intron 3 of 14	1	NM_000122.2	ENSP00000285398.2

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71245 AN: 151950 Hom.: 16993 Cov.: 32

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.474

GnomAD4 exome AF: 0.430 AC: 13578 AN: 31546 Hom.: 3373 Cov.: 0 AF XY: 0.423 AC XY: 6941 AN XY: 16416

African (AFR) AF: 0.465 AC: 607 AN: 1306

American (AMR) AF: 0.654 AC: 2246 AN: 3436

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 269 AN: 526

East Asian (EAS) AF: 0.610 AC: 1606 AN: 2632

South Asian (SAS) AF: 0.221 AC: 863 AN: 3908

European-Finnish (FIN) AF: 0.393 AC: 294 AN: 748

Middle Eastern (MID) AF: 0.487 AC: 37 AN: 76

European-Non Finnish (NFE) AF: 0.400 AC: 7029 AN: 17556

Other (OTH) AF: 0.462 AC: 627 AN: 1358

GnomAD4 genome AF: 0.469 AC: 71321 AN: 152070 Hom.: 17020 Cov.: 32 AF XY: 0.470 AC XY: 34928 AN XY: 74334

African (AFR) AF: 0.472 AC: 19589 AN: 41460

American (AMR) AF: 0.597 AC: 9131 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1855 AN: 3470

East Asian (EAS) AF: 0.618 AC: 3189 AN: 5162

South Asian (SAS) AF: 0.277 AC: 1335 AN: 4824

European-Finnish (FIN) AF: 0.446 AC: 4717 AN: 10576

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29959 AN: 67978

Other (OTH) AF: 0.469 AC: 989 AN: 2108

Alfa AF: 0.495 Hom.: 3098

Bravo AF: 0.488

Asia WGS AF: 0.457 AC: 1585 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.52
PhyloP100		-0.55
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: rs4150407; hg19: chr2-128049631; COSMIC: COSV53430279; COSMIC: COSV53430279;