2-219076557-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

• chr2-219076557-CT-C
• rs778354452
• NM_024782.3:c.826-103delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_024782.3(NHEJ1):​c.826-103delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 448,876 control chromosomes in the GnomAD database, including 8 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0042 (7 hom., cov: 28)
  • Exomes 𝑓: 0.20 (1 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00417 (511/122500) while in subpopulation AMR AF = 0.0108 (128/11812). AF 95% confidence interval is 0.00931. There are 7 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 509 AN: 122524 Hom.: 6 Cov.: 28

Gnomad AFR AF: 0.00663

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00370

Gnomad EAS AF: 0.00656

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.000979

Gnomad MID AF: 0.0119

Gnomad NFE AF: 0.00183

Gnomad OTH AF: 0.00423

GnomAD4 exome AF: 0.198 AC: 64617 AN: 326376 Hom.: 1 AF XY: 0.198 AC XY: 35479 AN XY: 179032

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

African (AFR) AF: 0.174 AC: 1492 AN: 8586

American (AMR) AF: 0.205 AC: 3074 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 1778 AN: 9502

East Asian (EAS) AF: 0.208 AC: 3689 AN: 17696

South Asian (SAS) AF: 0.198 AC: 8211 AN: 41528

European-Finnish (FIN) AF: 0.204 AC: 3357 AN: 16456

Middle Eastern (MID) AF: 0.185 AC: 234 AN: 1266

European-Non Finnish (NFE) AF: 0.198 AC: 39403 AN: 199344

Other (OTH) AF: 0.199 AC: 3379 AN: 17016

⚠️ 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: 0.00417 AC: 511 AN: 122500 Hom.: 7 Cov.: 28 AF XY: 0.00380 AC XY: 223 AN XY: 58634

African (AFR) AF: 0.00662 AC: 216 AN: 32638

American (AMR) AF: 0.0108 AC: 128 AN: 11812

Ashkenazi Jewish (ASJ) AF: 0.00370 AC: 11 AN: 2976

East Asian (EAS) AF: 0.00659 AC: 29 AN: 4400

South Asian (SAS) AF: 0.00129 AC: 5 AN: 3884

European-Finnish (FIN) AF: 0.000979 AC: 6 AN: 6128

Middle Eastern (MID) AF: 0.0130 AC: 3 AN: 230

European-Non Finnish (NFE) AF: 0.00183 AC: 106 AN: 57980

Other (OTH) AF: 0.00421 AC: 7 AN: 1662

Alfa AF: 0.00 Hom.: 57

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

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: rs778354452; hg19: chr2-219941279;