2-127280968-T-C

Variant names:

• chr2-127280968-T-C
• rs4150454
• NM_000122.2:c.1343-337A>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.1343-337A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 477,276 control chromosomes in the GnomAD database, including 41,526 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 0.37 (11286 hom., cov: 32)
  • Exomes 𝑓: 0.42 (30240 hom.)
• Consequence: ERCC3 NM_000122.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.941
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum group B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 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.1343-337A>G		intron	N/A	NP_000113.1	P19447
	ERCC3	NM_001303416.2		c.1151-337A>G		intron	N/A	NP_001290345.1
	ERCC3	NM_001303418.2		c.1151-337A>G		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.1343-337A>G		intron	N/A	ENSP00000285398.2	P19447
	ERCC3	ENST00000647169.1		c.1347A>G	p.Leu449Leu	synonymous	Exon 9 of 16	ENSP00000495619.1	A0A2R8Y6W8
	ERCC3	ENST00000918332.1		c.1394-337A>G		intron	N/A	ENSP00000588391.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56393 AN: 151932 Hom.: 11280 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.385

GnomAD4 exome AF: 0.422 AC: 137283 AN: 325224 Hom.: 30240 Cov.: 0 AF XY: 0.419 AC XY: 70185 AN XY: 167454

African (AFR) AF: 0.239 AC: 2192 AN: 9186

American (AMR) AF: 0.606 AC: 7401 AN: 12204

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 4723 AN: 10962

East Asian (EAS) AF: 0.680 AC: 18434 AN: 27106

South Asian (SAS) AF: 0.269 AC: 4060 AN: 15102

European-Finnish (FIN) AF: 0.420 AC: 9991 AN: 23788

Middle Eastern (MID) AF: 0.329 AC: 500 AN: 1518

European-Non Finnish (NFE) AF: 0.397 AC: 81492 AN: 205124

Other (OTH) AF: 0.420 AC: 8490 AN: 20234

GnomAD4 genome AF: 0.371 AC: 56417 AN: 152052 Hom.: 11286 Cov.: 32 AF XY: 0.375 AC XY: 27876 AN XY: 74316

African (AFR) AF: 0.239 AC: 9925 AN: 41468

American (AMR) AF: 0.536 AC: 8195 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1439 AN: 3466

East Asian (EAS) AF: 0.615 AC: 3181 AN: 5170

South Asian (SAS) AF: 0.259 AC: 1251 AN: 4824

European-Finnish (FIN) AF: 0.424 AC: 4470 AN: 10550

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26633 AN: 67972

Other (OTH) AF: 0.382 AC: 807 AN: 2112

Alfa AF: 0.379 Hom.: 5649

Bravo AF: 0.381

Asia WGS AF: 0.430 AC: 1493 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.5
DANN	Benign	0.77
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4150454; hg19: chr2-128038544;