Genetic Variant NHEJ1:c.826-107_826-103dupAAAAA (chr2-219076557-C-CTTTTT) – ACMG Classification: Uncertain_significance (2 pts)

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_826-103dupAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000597 in 335,174 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 0.0000082 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NHEJ1
NM_024782.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.188

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3 link	c.826-107_826-103dupAAAAA	intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1 link	c.841-107_841-103dupAAAAA	intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1 link	c.826-107_826-103dupAAAAA	intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1 link	n.1004-107_1004-103dupAAAAA	intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10 link	c.826-103_826-102insAAAAA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5		Q9H9Q4-1
ENSG00000280537	ENST00000318673.6 link	n.1948-103_1948-102insAAAAA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3		F8W735

Frequencies

GnomAD3 genomes

AF:

0.00000816

AC:

AN:

122534

Hom.:

Cov.:

show subpopulations

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:

0.0000172

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000597

AC:

AN:

335174

Hom.:

AF XY:

0.00

AC XY:

AN XY:

183988

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

8954

American (AMR)

AF:

0.00

AC:

AN:

15420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9718

East Asian (EAS)

AF:

0.00

AC:

AN:

18096

South Asian (SAS)

AF:

0.00

AC:

AN:

43208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1290

European-Non Finnish (NFE)

AF:

0.00000490

AC:

AN:

204176

Other (OTH)

AF:

0.0000574

AC:

AN:

17436

⚠️ 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: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000816

AC:

AN:

122534

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

58630

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32604

American (AMR)

AF:

0.00

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:

0.0000172

AC:

AN:

57998

Other (OTH)

AF:

0.00

AC:

AN:

1654

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000692

Hom.:

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

Publications

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2-219076557-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over