2-219077145-T-C

Variant names:

• chr2-219077145-T-C
• rs73991016
• NM_024782.3:c.825+101A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024782.3(NHEJ1):​c.825+101A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 860,256 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (69 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (30 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.318
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-219077145-T-C is Benign according to our data. Variant chr2-219077145-T-C is described in ClinVar as [Benign]. Clinvar id is 1258953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.825+101A>G		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.840+101A>G		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.825+101A>G		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1003+101A>G		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.825+101A>G		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1947+101A>G		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2459 AN: 152214 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

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: 0.000147

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00189 AC: 1335 AN: 707924 Hom.: 30 AF XY: 0.00151 AC XY: 571 AN XY: 378656

African (AFR) AF: 0.0525 AC: 997 AN: 18992

American (AMR) AF: 0.00366 AC: 150 AN: 40932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21168

East Asian (EAS) AF: 0.00 AC: 0 AN: 36100

South Asian (SAS) AF: 0.0000868 AC: 6 AN: 69150

European-Finnish (FIN) AF: 0.0000194 AC: 1 AN: 51514

Middle Eastern (MID) AF: 0.00106 AC: 3 AN: 2828

European-Non Finnish (NFE) AF: 0.000109 AC: 47 AN: 431606

Other (OTH) AF: 0.00368 AC: 131 AN: 35634

GnomAD4 genome AF: 0.0161 AC: 2458 AN: 152332 Hom.: 69 Cov.: 32 AF XY: 0.0153 AC XY: 1141 AN XY: 74500

African (AFR) AF: 0.0558 AC: 2320 AN: 41568

American (AMR) AF: 0.00653 AC: 100 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68028

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.0181

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: 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	-0.87
CADD	Benign	2.8
DANN	Benign	0.76
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs73991016; hg19: chr2-219941867;