rs4150403

Variant names:

• chr2-127292492-C-T
• rs4150403
• NM_000122.2:c.471+118G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000122.2(ERCC3):​c.471+118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0641 in 802,618 control chromosomes in the GnomAD database, including 2,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (334 hom., cov: 32)
  • Exomes 𝑓: 0.066 (1712 hom.)
• Consequence: ERCC3 NM_000122.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.699
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-127292492-C-T is Benign according to our data. Variant chr2-127292492-C-T is described in ClinVar as Benign. ClinVar VariationId is 1234691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0817 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000122.2. 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
	ERCC3	NM_000122.2	MANE Select	c.471+118G>A		intron	N/A	NP_000113.1
	ERCC3	NM_001303416.2		c.279+118G>A		intron	N/A	NP_001290345.1
	ERCC3	NM_001303418.2		c.279+118G>A		intron	N/A	NP_001290347.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC3	ENST00000285398.7	TSL:1 MANE Select	c.471+118G>A		intron	N/A	ENSP00000285398.2
	ERCC3	ENST00000462306.5	TSL:1	n.385+118G>A		intron	N/A
	ERCC3	ENST00000494464.5	TSL:1	n.355+118G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8566 AN: 152070 Hom.: 335 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0962

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0643

GnomAD4 exome AF: 0.0660 AC: 42918 AN: 650430 Hom.: 1712 Cov.: 8 AF XY: 0.0641 AC XY: 22656 AN XY: 353284

African (AFR) AF: 0.0158 AC: 288 AN: 18258

American (AMR) AF: 0.0310 AC: 1357 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 2001 AN: 21180

East Asian (EAS) AF: 0.000138 AC: 5 AN: 36202

South Asian (SAS) AF: 0.0176 AC: 1225 AN: 69506

European-Finnish (FIN) AF: 0.0974 AC: 4305 AN: 44192

Middle Eastern (MID) AF: 0.0777 AC: 201 AN: 2586

European-Non Finnish (NFE) AF: 0.0820 AC: 31232 AN: 380890

Other (OTH) AF: 0.0680 AC: 2304 AN: 33864

GnomAD4 genome AF: 0.0563 AC: 8562 AN: 152188 Hom.: 334 Cov.: 32 AF XY: 0.0547 AC XY: 4066 AN XY: 74392

African (AFR) AF: 0.0158 AC: 657 AN: 41534

American (AMR) AF: 0.0372 AC: 568 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 332 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4814

European-Finnish (FIN) AF: 0.0962 AC: 1019 AN: 10598

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0836 AC: 5682 AN: 68002

Other (OTH) AF: 0.0636 AC: 134 AN: 2106

Alfa AF: 0.0694 Hom.: 883

Bravo AF: 0.0506

Asia WGS AF: 0.00982 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.52
PhyloP100		0.70
PromoterAI		0.025	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4150403; hg19: chr2-128050068;