rs10498064

Variant names:

• chr2-219095357-T-A
• rs10498064
• NM_024782.3:c.589-17151A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-219095357-T-A
• chr2-219095357-T-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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)

ENSG00000280537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	NM_024782.3	MANE Select	c.589-17151A>T		intron	N/A	NP_079058.1
	NHEJ1	NM_001377499.1		c.589-17151A>T		intron	N/A	NP_001364428.1
	NHEJ1	NM_001377498.1		c.589-17151A>T		intron	N/A	NP_001364427.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.589-17151A>T		intron	N/A	ENSP00000349313.5
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1711-17151A>T		intron	N/A	ENSP00000320919.3
	NHEJ1	ENST00000409720.5	TSL:5	c.589-17151A>T		intron	N/A	ENSP00000387290.1

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

GnomAD2 exomes AF: 0.0101 AC: 1475 AN: 146252 AF XY: 0.00831

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 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

African (AFR) AF: 0.153 AC: 1320 AN: 8612

American (AMR) AF: 0.00789 AC: 215 AN: 27264

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 152 AN: 10782

East Asian (EAS) AF: 0.00 AC: 0 AN: 9210

South Asian (SAS) AF: 0.000285 AC: 17 AN: 59700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27052

Middle Eastern (MID) AF: 0.00396 AC: 11 AN: 2778

European-Non Finnish (NFE) AF: 0.000183 AC: 29 AN: 158850

Other (OTH) AF: 0.00895 AC: 128 AN: 14304

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

African (AFR) AF: 0.147 AC: 6085 AN: 41490

American (AMR) AF: 0.0177 AC: 271 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67994

Other (OTH) AF: 0.0392 AC: 83 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.4
DANN	Benign	0.59
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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