rs16859517

Variant names:

• chr2-219084462-C-T
• rs16859517
• NM_024782.3:c.589-6256G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024782.3(NHEJ1):​c.589-6256G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 152,262 control chromosomes in the GnomAD database, including 869 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.060 (869 hom., cov: 31)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.632
• Publications: 28 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024782.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	NM_024782.3	MANE Select	c.589-6256G>A		intron	N/A	NP_079058.1
	NHEJ1	NM_001377499.1		c.589-6256G>A		intron	N/A	NP_001364428.1
	NHEJ1	NM_001377498.1		c.589-6256G>A		intron	N/A	NP_001364427.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.589-6256G>A		intron	N/A	ENSP00000349313.5
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1711-6256G>A		intron	N/A	ENSP00000320919.3
	NHEJ1	ENST00000409720.5	TSL:5	c.589-6256G>A		intron	N/A	ENSP00000387290.1

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9065 AN: 152144 Hom.: 867 Cov.: 31

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.0935

Gnomad FIN AF: 0.0543

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.0664

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0597 AC: 9083 AN: 152262 Hom.: 869 Cov.: 31 AF XY: 0.0655 AC XY: 4873 AN XY: 74438

African (AFR) AF: 0.0174 AC: 722 AN: 41562

American (AMR) AF: 0.154 AC: 2354 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.461 AC: 2377 AN: 5160

South Asian (SAS) AF: 0.0939 AC: 453 AN: 4822

European-Finnish (FIN) AF: 0.0543 AC: 577 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0345 AC: 2349 AN: 68022

Other (OTH) AF: 0.0719 AC: 152 AN: 2114

Alfa AF: 0.0505 Hom.: 2637

Bravo AF: 0.0694

Asia WGS AF: 0.282 AC: 977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.7
DANN	Benign	0.58
PhyloP100		0.63
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: rs16859517; hg19: chr2-219949184;