2-219076557-CTTTTTTTTTTTTTT-CTTTTTTTTT

Variant names:

• chr2-219076557-CTTTTT-C
• rs778354452
• NM_024782.3:c.826-107_826-103delAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024782.3(NHEJ1):​c.826-107_826-103delAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 331,490 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 0.0 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.16
• 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 2 ACMG points.

• PM2: Variant has high frequency in the EAS (0.00631) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.826-107_826-103delAAAAA		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.841-107_841-103delAAAAA		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.826-107_826-103delAAAAA		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1004-107_1004-103delAAAAA		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.826-107_826-103delAAAAA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1948-107_*1948-103delAAAAA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 122534 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

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: 0.00479 AC: 1587 AN: 331490 Hom.: 0 AF XY: 0.00452 AC XY: 822 AN XY: 181932

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

African (AFR) AF: 0.00439 AC: 39 AN: 8874

American (AMR) AF: 0.00413 AC: 63 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00614 AC: 59 AN: 9616

East Asian (EAS) AF: 0.00733 AC: 131 AN: 17868

South Asian (SAS) AF: 0.00105 AC: 45 AN: 42732

European-Finnish (FIN) AF: 0.00564 AC: 94 AN: 16670

Middle Eastern (MID) AF: 0.00547 AC: 7 AN: 1280

European-Non Finnish (NFE) AF: 0.00524 AC: 1058 AN: 201966

Other (OTH) AF: 0.00528 AC: 91 AN: 17238

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 122510 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 58638

African (AFR) AF: 0.00 AC: 0 AN: 32644

American (AMR) AF: 0.00 AC: 0 AN: 11812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2976

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: 6128

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57984

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=99/1	polymorphism

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;