rs7585742

Variant names:

• chr2-219147854-G-C
• rs7585742
• NM_024782.3:c.391-59C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

NHEJ1 Gene-Disease associations (from GenCC):

• Cernunnos-XLF deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000280537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.391-59C>G		intron_variant	Intron 3 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.391-59C>G		intron_variant	Intron 3 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.391-59C>G		intron_variant	Intron 3 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.487-59C>G		intron_variant	Intron 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.391-59C>G		intron_variant	Intron 3 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1513-59C>G		intron_variant	Intron 12 of 16	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

African (AFR) AF: 0.239 AC: 7762 AN: 32464

American (AMR) AF: 0.481 AC: 21027 AN: 43724

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 14934 AN: 25802

East Asian (EAS) AF: 0.279 AC: 10999 AN: 39360

South Asian (SAS) AF: 0.560 AC: 47435 AN: 84656

European-Finnish (FIN) AF: 0.695 AC: 36301 AN: 52216

Middle Eastern (MID) AF: 0.521 AC: 2898 AN: 5566

European-Non Finnish (NFE) AF: 0.644 AC: 694489 AN: 1078422

Other (OTH) AF: 0.569 AC: 33572 AN: 58968

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

African (AFR) AF: 0.252 AC: 10439 AN: 41478

American (AMR) AF: 0.487 AC: 7449 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1985 AN: 3470

East Asian (EAS) AF: 0.298 AC: 1543 AN: 5180

South Asian (SAS) AF: 0.547 AC: 2641 AN: 4826

European-Finnish (FIN) AF: 0.698 AC: 7372 AN: 10568

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43369 AN: 67994

Other (OTH) AF: 0.479 AC: 1010 AN: 2110

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.3
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: rs7585742; hg19: chr2-220012576;