chr2-219095357-T-A

Position:

• chr2-219095357-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024782.3(NHEJ1):​c.589-17151A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 470,770 control chromosomes in the GnomAD database, including 593 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 0.043 (472 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (121 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Scores: Splicing: ADA: 0.00003395
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.589-17151A>T		intron_variant		ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377498.1	c.589-17151A>T		intron_variant			NP_001364427.1
NHEJ1	NM_001377499.1	c.589-17151A>T		intron_variant			NP_001364428.1
NHEJ1	NR_165304.1	n.685-2A>T		splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.589-17151A>T		intron_variant		1	NM_024782.3	ENSP00000349313	P4

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6504 AN: 152100 Hom.: 471 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0396

GnomAD3 exomes AF: 0.0101 AC: 1475 AN: 146252 Hom.: 97 AF XY: 0.00831 AC XY: 656 AN XY: 78906

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.00765

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.00779

GnomAD4 exome AF: 0.00588 AC: 1872 AN: 318552 Hom.: 121 Cov.: 0 AF XY: 0.00458 AC XY: 824 AN XY: 180000

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.00789

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000285

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.00895

GnomAD4 genome AF: 0.0428 AC: 6513 AN: 152218 Hom.: 472 Cov.: 32 AF XY: 0.0406 AC XY: 3025 AN XY: 74432

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0392

Alfa AF: 0.00387 Hom.: 8

Bravo AF: 0.0482

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.4
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: -9

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

Publications

LitVar

Other links and lift over

dbSNP: rs10498064; hg19: chr2-219960079; COSMIC: COSV59430707;