Genetic Variant NHEJ1:c.826-109_826-103delAAAAAAA (chr2-219076557-CTTTTTTT-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_024782.3(NHEJ1):c.826-109_826-103delAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 457,426 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 0.000033 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

NHEJ1
NM_024782.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.16

Publications

0 publications found

Variant links:

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)

NHEJ1 links:

ENSG00000280537 (HGNC:):

ENSG00000280537 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000326 (4/122536) while in subpopulation AMR AF = 0.000254 (3/11814). AF 95% confidence interval is 0.000069. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3 link	c.826-109_826-103delAAAAAAA	intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1 link	c.841-109_841-103delAAAAAAA	intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1 link	c.826-109_826-103delAAAAAAA	intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1 link	n.1004-109_1004-103delAAAAAAA	intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10 link	c.826-109_826-103delAAAAAAA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5		Q9H9Q4-1
ENSG00000280537	ENST00000318673.6 link	n.1948-109_1948-103delAAAAAAA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3		F8W735

Frequencies

GnomAD3 genomes

AF:

0.0000326

AC:

AN:

122536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000307

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000254

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:

0.000502

AC:

168

AN:

334890

Hom.:

AF XY:

0.000462

AC XY:

AN XY:

183824

show subpopulations

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

African (AFR)

AF:

0.000670

AC:

AN:

8952

American (AMR)

AF:

0.000714

AC:

AN:

15412

Ashkenazi Jewish (ASJ)

AF:

0.000721

AC:

AN:

9706

East Asian (EAS)

AF:

0.000885

AC:

AN:

18076

South Asian (SAS)

AF:

0.0000232

AC:

AN:

43184

European-Finnish (FIN)

AF:

0.000593

AC:

AN:

16872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1290

European-Non Finnish (NFE)

AF:

0.000515

AC:

105

AN:

203982

Other (OTH)

AF:

0.000689

AC:

AN:

17416

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.262

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000326

AC:

AN:

122536

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

58630

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32606

American (AMR)

AF:

0.000254

AC:

AN:

11814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2976

East Asian (EAS)

AF:

0.00

AC:

AN:

4418

South Asian (SAS)

AF:

0.00

AC:

AN:

3900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57998

Other (OTH)

AF:

0.00

AC:

AN:

1654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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2-219076557-CTTTTTTTTTTTTTT-CTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over