rs113689741

Variant names:

• chr2-219157604-G-A
• rs113689741
• NM_024782.3:c.258C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-219157604-G-A
• chr2-219157604-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_024782.3(NHEJ1):​c.258C>T​(p.Asp86Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,614,154 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: NHEJ1 NM_024782.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.43

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]

ENSG00000280537 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-219157604-G-A is Benign according to our data. Variant chr2-219157604-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211594.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr2-219157604-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00227 (345/152298) while in subpopulation AFR AF= 0.00792 (329/41552). AF 95% confidence interval is 0.00721. There are 1 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.258C>T	p.Asp86Asp	synonymous_variant	Exon 3 of 8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.258C>T	p.Asp86Asp	synonymous_variant	Exon 3 of 8		NP_001364428.1
NHEJ1	NM_001377498.1	c.258C>T	p.Asp86Asp	synonymous_variant	Exon 3 of 8		NP_001364427.1
NHEJ1	NR_165304.1	n.354C>T		non_coding_transcript_exon_variant	Exon 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.258C>T	p.Asp86Asp	synonymous_variant	Exon 3 of 8	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1380C>T		non_coding_transcript_exon_variant	Exon 12 of 17	2		ENSP00000320919.3
ENSG00000280537	ENST00000318673.6	n.*1380C>T		3_prime_UTR_variant	Exon 12 of 17	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00792

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000441

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000640 AC: 161 AN: 251394 Hom.: 1 AF XY: 0.000456 AC XY: 62 AN XY: 135868

Gnomad AFR exome AF: 0.00874

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000276 AC: 404 AN: 1461856 Hom.: 1 Cov.: 36 AF XY: 0.000237 AC XY: 172 AN XY: 727232

Gnomad4 AFR exome AF: 0.00887

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00227 AC: 345 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74460

Gnomad4 AFR AF: 0.00792

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000863 Hom.: 1

Bravo AF: 0.00260

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NHEJ1-related disorder Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cernunnos-XLF deficiency Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.2
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs113689741; hg19: chr2-220022326;