rs7585742

Positions:

• chr2-219147854-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024782.3(NHEJ1):​c.391-59C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,573,286 control chromosomes in the GnomAD database, including 293,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21570 hom., cov: 33)
  • Exomes 𝑓: 0.61 (272006 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.32

Genes affected

NHEJ1 (HGNC:25737): (non-homologous end joining factor 1) Double-strand breaks in DNA result from genotoxic stresses and are among the most damaging of DNA lesions. This gene encodes a DNA repair factor essential for the nonhomologous end-joining pathway, which preferentially mediates repair of double-stranded breaks. Mutations in this gene cause different kinds of severe combined immunodeficiency disorders. [provided by RefSeq, Jul 2008]

ENSG00000280537 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-219147854-G-C is Benign according to our data. Variant chr2-219147854-G-C is described in ClinVar as [Benign]. Clinvar id is 1243280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.391-59C>G		intron_variant		ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.391-59C>G		intron_variant			NP_001364428.1
NHEJ1	NM_001377498.1	c.391-59C>G		intron_variant			NP_001364427.1
NHEJ1	NR_165304.1	n.487-59C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.391-59C>G		intron_variant		1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1513-59C>G		intron_variant		2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76427 AN: 151992 Hom.: 21570 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.485

GnomAD4 exome AF: 0.612 AC: 869417 AN: 1421178 Hom.: 272006 AF XY: 0.612 AC XY: 433586 AN XY: 708858

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.481

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.560

Gnomad4 FIN exome AF: 0.695

Gnomad4 NFE exome AF: 0.644

Gnomad4 OTH exome AF: 0.569

GnomAD4 genome AF: 0.502 AC: 76430 AN: 152108 Hom.: 21570 Cov.: 33 AF XY: 0.505 AC XY: 37574 AN XY: 74338

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.487

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.547

Gnomad4 FIN AF: 0.698

Gnomad4 NFE AF: 0.638

Gnomad4 OTH AF: 0.479

Alfa AF: 0.571 Hom.: 3310

Bravo AF: 0.473

Asia WGS AF: 0.337 AC: 1174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.16
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs7585742; hg19: chr2-220012576;