2-219076557-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTT

Variant names:

• chr2-219076557-C-CTTT
• rs778354452
• NM_024782.3:c.826-105_826-103dupAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_024782.3(NHEJ1):​c.826-105_826-103dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 457,026 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.188
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.826-105_826-103dupAAA		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.841-105_841-103dupAAA		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.826-105_826-103dupAAA		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1004-105_1004-103dupAAA		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.826-103_826-102insAAA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1948-103_*1948-102insAAA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.0000163 AC: 2 AN: 122516 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000307

Gnomad AMI AF: 0.00127

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000377 AC: 126 AN: 334534 Hom.: 0 AF XY: 0.000354 AC XY: 65 AN XY: 183642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00112 AC: 10 AN: 8930

American (AMR) AF: 0.000325 AC: 5 AN: 15398

Ashkenazi Jewish (ASJ) AF: 0.000515 AC: 5 AN: 9706

East Asian (EAS) AF: 0.000277 AC: 5 AN: 18066

South Asian (SAS) AF: 0.000348 AC: 15 AN: 43096

European-Finnish (FIN) AF: 0.000119 AC: 2 AN: 16852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1288

European-Non Finnish (NFE) AF: 0.000373 AC: 76 AN: 203798

Other (OTH) AF: 0.000460 AC: 8 AN: 17400

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000163 AC: 2 AN: 122492 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 58628

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000306 AC: 1 AN: 32642

American (AMR) AF: 0.00 AC: 0 AN: 11806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2974

East Asian (EAS) AF: 0.00 AC: 0 AN: 4400

South Asian (SAS) AF: 0.00 AC: 0 AN: 3884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57980

Other (OTH) AF: 0.00 AC: 0 AN: 1662

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000980 Hom.: 57

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs778354452; hg19: chr2-219941279;