Genetic Variant NHEJ1:c.*6755C>A (chr2-219069626-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024782.3(NHEJ1):c.*6755C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,240 control chromosomes in the GnomAD database, including 1,349 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 1349 hom., cov: 32)

Exomes 𝑓: 0.11 ( 0 hom. )

Consequence

NHEJ1
NM_024782.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.655

Publications

23 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:

ENSG00000286606 (HGNC:):

ENSG00000286606 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

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
NHEJ1	NM_024782.3	MANE Select	c.*6755C>A	3_prime_UTR	Exon 8 of 8	NP_079058.1
NHEJ1	NR_165304.1		n.7833C>A	non_coding_transcript_exon	Exon 9 of 9
NHEJ1	NM_001377499.1		c.*6755C>A	3_prime_UTR	Exon 8 of 8	NP_001364428.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.*6755C>A	3_prime_UTR	Exon 8 of 8	ENSP00000349313.5
ENSG00000286606	ENST00000666065.1		n.867G>T	non_coding_transcript_exon	Exon 3 of 3
NHEJ1	ENST00000698174.1		n.*2393C>A	non_coding_transcript_exon	Exon 9 of 9	ENSP00000513594.1

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19161

AN:

152102

Hom.:

1342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.0617

Gnomad FIN

AF:

0.0825

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0977

Gnomad OTH

AF:

0.127

GnomAD4 exome

AF:

0.111

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0833

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.126

AC:

19196

AN:

152222

Hom.:

1349

Cov.:

AF XY:

0.124

AC XY:

9231

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.199

AC:

8259

AN:

41498

American (AMR)

AF:

0.105

AC:

1601

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

357

AN:

3468

East Asian (EAS)

AF:

0.145

AC:

754

AN:

5190

South Asian (SAS)

AF:

0.0619

AC:

299

AN:

4828

European-Finnish (FIN)

AF:

0.0825

AC:

875

AN:

10600

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0977

AC:

6648

AN:

68026

Other (OTH)

AF:

0.128

AC:

270

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

851

1702

2553

3404

4255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.108

Hom.:

3196

Bravo

AF:

0.134

Asia WGS

AF:

0.129

AC:

448

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

3.9

(source)

DANN

Benign

0.78

PhyloP100

-0.66

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over