Genetic Variant NHEJ1:c.826-105_826-103dupAAA (chr2-219076557-C-CTTT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_024782.3(NHEJ1):c.826-105_826-103dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 457,026 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 0.000016 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00038 ( 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

NHEJ1 links:

ENSG00000280537 (HGNC:):

ENSG00000280537 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024782.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NHEJ1	NM_024782.3	MANE Select	c.826-105_826-103dupAAA	intron	N/A	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1		c.841-105_841-103dupAAA	intron	N/A	NP_001364428.1	H7C0G7
NHEJ1	NM_001377498.1		c.826-105_826-103dupAAA	intron	N/A	NP_001364427.1	Q9H9Q4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.826-103_826-102insAAA	intron	N/A	ENSP00000349313.5	Q9H9Q4-1
ENSG00000280537	ENST00000318673.6	TSL:2	n.1948-103_1948-102insAAA	intron	N/A	ENSP00000320919.3	F8W735
NHEJ1	ENST00000881108.1		c.892-103_892-102insAAA	intron	N/A	ENSP00000551167.1

Frequencies

GnomAD3 genomes

AF:

0.0000163

AC:

AN:

122516

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000307

Gnomad AMI

AF:

0.00127

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:

0.000377

AC:

126

AN:

334534

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

183642

show subpopulations

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

African (AFR)

AF:

0.00112

AC:

AN:

8930

American (AMR)

AF:

0.000325

AC:

AN:

15398

Ashkenazi Jewish (ASJ)

AF:

0.000515

AC:

AN:

9706

East Asian (EAS)

AF:

0.000277

AC:

AN:

18066

South Asian (SAS)

AF:

0.000348

AC:

AN:

43096

European-Finnish (FIN)

AF:

0.000119

AC:

AN:

16852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1288

European-Non Finnish (NFE)

AF:

0.000373

AC:

AN:

203798

Other (OTH)

AF:

0.000460

AC:

AN:

17400

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000163

AC:

AN:

122492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

58628

show subpopulations

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

African (AFR)

AF:

0.0000306

AC:

AN:

32642

American (AMR)

AF:

0.00

AC:

AN:

11806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2974

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:

6124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57980

Other (OTH)

AF:

0.00

AC:

AN:

1662

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), 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

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000980

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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-CTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over