19-45413645-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The ENST00000013807.9(ERCC1):c.875G>A(p.Trp292Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,236 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (25 hom.)
• Consequence: ERCC1 ENST00000013807.9 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.29

Genes affected

ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0998 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 19-45413645-C-T is Benign according to our data. Variant chr19-45413645-C-T is described in ClinVar as [Benign]. Clinvar id is 329534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45413645-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00706 (1075/152354) while in subpopulation AFR AF= 0.0249 (1034/41582). AF 95% confidence interval is 0.0236. There are 14 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC1	NM_001983.4	c.843+32G>A		intron_variant		ENST00000300853.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC1	ENST00000300853.8	c.843+32G>A		intron_variant		1	NM_001983.4	P1

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1072 AN: 152236 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00201 AC: 506 AN: 251486 Hom.: 4 AF XY: 0.00151 AC XY: 205 AN XY: 135920

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000806 AC: 1179 AN: 1461882 Hom.: 25 Cov.: 31 AF XY: 0.000751 AC XY: 546 AN XY: 727244

Gnomad4 AFR exome AF: 0.0262

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00706 AC: 1075 AN: 152354 Hom.: 14 Cov.: 32 AF XY: 0.00656 AC XY: 489 AN XY: 74494

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00128 Hom.: 4

Bravo AF: 0.00785

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00248 AC: 301

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ERCC1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2019	This variant is associated with the following publications: (PMID: 29868112) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

Cerebrooculofacioskeletal syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jan 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	0.11
Dann	Benign	0.61
Eigen	Benign	-0.69
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
MutationTaster	Benign	1.0	D;N;N;N;N;N
Vest4		0.17
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs116640350; hg19: chr19-45916903;