2-219077217-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024782.3(NHEJ1):c.825+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,549,942 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (259 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.54

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-219077217-C-T is Benign according to our data. Variant chr2-219077217-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1200626.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-219077217-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2168/152312) while in subpopulation NFE AF= 0.022 (1495/68028). AF 95% confidence interval is 0.021. There are 22 homozygotes in gnomad4. There are 1042 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHEJ1	NM_024782.3	c.825+29G>A		intron_variant		ENST00000356853.10
NHEJ1	NM_001377498.1	c.825+29G>A		intron_variant
NHEJ1	NM_001377499.1	c.840+29G>A		intron_variant
NHEJ1	NR_165304.1	n.1003+29G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHEJ1	ENST00000356853.10	c.825+29G>A		intron_variant		1	NM_024782.3	P4

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2169 AN: 152194 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0220

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0153 AC: 3847 AN: 251018 Hom.: 41 AF XY: 0.0154 AC XY: 2091 AN XY: 135676

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00790

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00657

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0181 AC: 25333 AN: 1397630 Hom.: 259 Cov.: 24 AF XY: 0.0177 AC XY: 12358 AN XY: 699372

Gnomad4 AFR exome AF: 0.00256

Gnomad4 AMR exome AF: 0.00784

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00602

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0142 AC: 2168 AN: 152312 Hom.: 22 Cov.: 32 AF XY: 0.0140 AC XY: 1042 AN XY: 74490

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.0220

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0196 Hom.: 8

Bravo AF: 0.0119

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.18
Dann	Benign	0.71

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: rs115483157; hg19: chr2-219941939;