Genetic Variant NHEJ1:c.826-113_826-103delAAAAAAAAAAA (chr2-219076557-CTTTTTTTTTTT-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.826-113_826-103delAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000918 in 457,686 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000024 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00012 ( 1 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 afr. GnomAdExome4 allele frequency = 0.000116 (39/335174) while in subpopulation AFR AF = 0.00257 (23/8934). AF 95% confidence interval is 0.00176. There are 1 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3 link	c.826-113_826-103delAAAAAAAAAAA	intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1 link	c.841-113_841-103delAAAAAAAAAAA	intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1 link	c.826-113_826-103delAAAAAAAAAAA	intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1 link	n.1004-113_1004-103delAAAAAAAAAAA	intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10 link	c.826-113_826-103delAAAAAAAAAAA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5		Q9H9Q4-1
ENSG00000280537	ENST00000318673.6 link	n.1948-113_1948-103delAAAAAAAAAAA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3		F8W735

Frequencies

GnomAD3 genomes

AF:

0.0000245

AC:

AN:

122536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000920

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:

0.000116

AC:

AN:

335174

Hom.:

AF XY:

0.0000707

AC XY:

AN XY:

183988

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

8934

American (AMR)

AF:

0.0000649

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:

43216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1290

European-Non Finnish (NFE)

AF:

0.0000490

AC:

AN:

204184

Other (OTH)

AF:

0.000287

AC:

AN:

17436

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000245

AC:

AN:

122512

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

58640

show subpopulations

African (AFR)

AF:

0.0000919

AC:

AN:

32646

American (AMR)

AF:

0.00

AC:

AN:

11812

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2976

East Asian (EAS)

AF:

0.00

AC:

AN:

4400

South Asian (SAS)

AF:

0.00

AC:

AN:

3884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57984

Other (OTH)

AF:

0.00

AC:

AN:

1662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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

Splicing

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

Publications

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2-219076557-CTTTTTTTTTTTTTT-CTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over