2-127288972-C-A

Variant names:

• chr2-127288972-C-A
• rs4150416
• NM_000122.2:c.823-108G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000122.2(ERCC3):​c.823-108G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 936,498 control chromosomes in the GnomAD database, including 225,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (34350 hom., cov: 32)
  • Exomes 𝑓: 0.69 (191128 hom.)
• Consequence: ERCC3 NM_000122.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.35
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-127288972-C-A is Benign according to our data. Variant chr2-127288972-C-A is described in ClinVar as Benign. ClinVar VariationId is 1245290.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC3	NM_000122.2	c.823-108G>T		intron_variant	Intron 6 of 14	ENST00000285398.7	NP_000113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC3	ENST00000285398.7	c.823-108G>T		intron_variant	Intron 6 of 14	1	NM_000122.2	ENSP00000285398.2

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101201 AN: 151972 Hom.: 34321 Cov.: 32

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.666

GnomAD4 exome AF: 0.691 AC: 542260 AN: 784408 Hom.: 191128 AF XY: 0.690 AC XY: 286820 AN XY: 415844

African (AFR) AF: 0.555 AC: 11332 AN: 20408

American (AMR) AF: 0.825 AC: 34107 AN: 41340

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 13174 AN: 21916

East Asian (EAS) AF: 0.999 AC: 36506 AN: 36556

South Asian (SAS) AF: 0.692 AC: 49472 AN: 71460

European-Finnish (FIN) AF: 0.729 AC: 36433 AN: 50002

Middle Eastern (MID) AF: 0.617 AC: 1766 AN: 2862

European-Non Finnish (NFE) AF: 0.664 AC: 333357 AN: 501730

Other (OTH) AF: 0.685 AC: 26113 AN: 38134

GnomAD4 genome AF: 0.666 AC: 101286 AN: 152090 Hom.: 34350 Cov.: 32 AF XY: 0.674 AC XY: 50079 AN XY: 74346

African (AFR) AF: 0.562 AC: 23317 AN: 41454

American (AMR) AF: 0.759 AC: 11619 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2088 AN: 3468

East Asian (EAS) AF: 0.995 AC: 5142 AN: 5166

South Asian (SAS) AF: 0.708 AC: 3409 AN: 4816

European-Finnish (FIN) AF: 0.741 AC: 7833 AN: 10572

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45706 AN: 68004

Other (OTH) AF: 0.669 AC: 1408 AN: 2104

Alfa AF: 0.665 Hom.: 11898

Bravo AF: 0.665

Asia WGS AF: 0.848 AC: 2945 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 10, 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	-0.89
CADD	Benign	0.024
DANN	Benign	0.50
PhyloP100		-2.4
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: rs4150416; hg19: chr2-128046548;