Genetic Variant NHEJ1:c.826-104_826-103dupAA (chr2-219076557-C-CTT) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS1

The NM_024782.3(NHEJ1):c.826-104_826-103dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 453,980 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 0.00089 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0051 ( 0 hom. )

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: Likely_benign. The variant received -2 ACMG points.

PM2

Variant has high frequency in the AFR (0.00634) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00089 (109/122470) while in subpopulation NFE AF = 0.00131 (76/57962). AF 95% confidence interval is 0.00107. There are 0 homozygotes in GnomAd4. There are 47 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.826-104_826-103dupAA	intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1 link	c.841-104_841-103dupAA	intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1 link	c.826-104_826-103dupAA	intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1 link	n.1004-104_1004-103dupAA	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_826-102insAA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5		Q9H9Q4-1
ENSG00000280537	ENST00000318673.6 link	n.1948-103_1948-102insAA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3		F8W735

Frequencies

GnomAD3 genomes

AF:

0.000890

AC:

109

AN:

122494

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000508

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000453

Gnomad SAS

AF:

0.000257

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00397

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00505

AC:

1675

AN:

331510

Hom.:

AF XY:

0.00507

AC XY:

923

AN XY:

181980

show subpopulations

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

African (AFR)

AF:

0.00782

AC:

AN:

8820

American (AMR)

AF:

0.00544

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00363

AC:

AN:

9638

East Asian (EAS)

AF:

0.00345

AC:

AN:

17966

South Asian (SAS)

AF:

0.00654

AC:

278

AN:

42516

European-Finnish (FIN)

AF:

0.00335

AC:

AN:

16728

Middle Eastern (MID)

AF:

0.00235

AC:

AN:

1276

European-Non Finnish (NFE)

AF:

0.00492

AC:

995

AN:

202054

Other (OTH)

AF:

0.00545

AC:

AN:

17256

⚠️ 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: 0.258

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000890

AC:

109

AN:

122470

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

AN XY:

58630

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

32638

American (AMR)

AF:

0.000508

AC:

AN:

11806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2974

East Asian (EAS)

AF:

0.000455

AC:

AN:

4400

South Asian (SAS)

AF:

0.000258

AC:

AN:

3882

European-Finnish (FIN)

AF:

0.000163

AC:

AN:

6128

Middle Eastern (MID)

AF:

0.00435

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

57962

Other (OTH)

AF:

0.00

AC:

AN:

1660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00161

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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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