chr2-127257337-C-T

Variant names:

• chr2-127257337-C-T
• rs1803541
• NM_000122.2:c.*259G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000122.2(ERCC3):​c.*259G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 522,666 control chromosomes in the GnomAD database, including 516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (126 hom., cov: 32)
  • Exomes 𝑓: 0.039 (390 hom.)
• Consequence: ERCC3 NM_000122.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00300
• Publications: 14 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• 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=-0.93).
• BP6: Variant 2-127257337-C-T is Benign according to our data. Variant chr2-127257337-C-T is described in ClinVar as Benign. ClinVar VariationId is 331068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0339 (5157/152216) while in subpopulation NFE AF = 0.0478 (3252/67996). AF 95% confidence interval is 0.0465. There are 126 homozygotes in GnomAd4. There are 2413 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 126 AR,AD gene

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.*259G>A		3_prime_UTR	Exon 15 of 15	NP_000113.1	P19447
	ERCC3	NM_001303416.2		c.*259G>A		3_prime_UTR	Exon 15 of 15	NP_001290345.1
	ERCC3	NM_001303418.2		c.*259G>A		3_prime_UTR	Exon 15 of 15	NP_001290347.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC3	ENST00000285398.7	TSL:1 MANE Select	c.*259G>A		3_prime_UTR	Exon 15 of 15	ENSP00000285398.2	P19447
	ERCC3	ENST00000647169.1		c.*259G>A		3_prime_UTR	Exon 16 of 16	ENSP00000495619.1	A0A2R8Y6W8
	ERCC3	ENST00000918332.1		c.*259G>A		3_prime_UTR	Exon 15 of 15	ENSP00000588391.1

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5159 AN: 152098 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0368

GnomAD4 exome AF: 0.0391 AC: 14479 AN: 370450 Hom.: 390 Cov.: 2 AF XY: 0.0387 AC XY: 7548 AN XY: 195078

African (AFR) AF: 0.0139 AC: 152 AN: 10958

American (AMR) AF: 0.0316 AC: 502 AN: 15904

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 1270 AN: 11436

East Asian (EAS) AF: 0.00 AC: 0 AN: 23930

South Asian (SAS) AF: 0.0164 AC: 714 AN: 43548

European-Finnish (FIN) AF: 0.0244 AC: 742 AN: 30386

Middle Eastern (MID) AF: 0.0560 AC: 86 AN: 1536

European-Non Finnish (NFE) AF: 0.0476 AC: 10092 AN: 211908

Other (OTH) AF: 0.0442 AC: 921 AN: 20844

GnomAD4 genome AF: 0.0339 AC: 5157 AN: 152216 Hom.: 126 Cov.: 32 AF XY: 0.0324 AC XY: 2413 AN XY: 74430

African (AFR) AF: 0.0132 AC: 549 AN: 41534

American (AMR) AF: 0.0339 AC: 518 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0163 AC: 79 AN: 4832

European-Finnish (FIN) AF: 0.0218 AC: 231 AN: 10584

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3252 AN: 67996

Other (OTH) AF: 0.0360 AC: 76 AN: 2112

Alfa AF: 0.0454 Hom.: 128

Bravo AF: 0.0338

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Xeroderma pigmentosum group B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.56
PhyloP100		0.0030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs1803541; hg19: chr2-128014913;