2-219076224-G-A

Position:

• chr2-219076224-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024782.3(NHEJ1):​c.*157C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,508,130 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (106 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (85 hom.)
• Consequence: NHEJ1 NM_024782.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.769

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-219076224-G-A is Benign according to our data. Variant chr2-219076224-G-A is described in ClinVar as [Benign]. Clinvar id is 1229618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.*157C>T		3_prime_UTR_variant	8/8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377498.1	c.*157C>T		3_prime_UTR_variant	8/8		NP_001364427.1
NHEJ1	NM_001377499.1	c.*157C>T		3_prime_UTR_variant	8/8		NP_001364428.1
NHEJ1	NR_165304.1	n.1235C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.*157C>T		3_prime_UTR_variant	8/8	1	NM_024782.3	ENSP00000349313	P4

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2898 AN: 152182 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00196 AC: 2659 AN: 1355830 Hom.: 85 Cov.: 25 AF XY: 0.00170 AC XY: 1137 AN XY: 668516

Gnomad4 AFR exome AF: 0.0681

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000315

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome AF: 0.0191 AC: 2907 AN: 152300 Hom.: 106 Cov.: 32 AF XY: 0.0185 AC XY: 1381 AN XY: 74478

Gnomad4 AFR AF: 0.0659

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00792 Hom.: 6

Bravo AF: 0.0222

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.19
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs79018048; hg19: chr2-219940946;