chr2-219077371-T-A

Variant names:

• chr2-219077371-T-A
• rs150521220
• NM_024782.3:c.707-7A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_024782.3(NHEJ1):​c.707-7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,592,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: NHEJ1 NM_024782.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001132
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.354
• 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000280537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-219077371-T-A is Benign according to our data. Variant chr2-219077371-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00164 (249/152244) while in subpopulation AFR AF = 0.00542 (225/41536). AF 95% confidence interval is 0.00484. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	NM_024782.3	MANE Select	c.707-7A>T		splice_region intron	N/A	NP_079058.1	Q9H9Q4-1
	NHEJ1	NM_001377499.1		c.722-7A>T		splice_region intron	N/A	NP_001364428.1	H7C0G7
	NHEJ1	NM_001377498.1		c.707-7A>T		splice_region intron	N/A	NP_001364427.1	Q9H9Q4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.707-7A>T		splice_region intron	N/A	ENSP00000349313.5	Q9H9Q4-1
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1829-7A>T		splice_region intron	N/A	ENSP00000320919.3	F8W735
	NHEJ1	ENST00000881108.1		c.773-7A>T		splice_region intron	N/A	ENSP00000551167.1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000441 AC: 111 AN: 251480 AF XY: 0.000316

Gnomad AFR exome AF: 0.00627

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000168 AC: 242 AN: 1439788 Hom.: 0 Cov.: 26 AF XY: 0.000135 AC XY: 97 AN XY: 717954

African (AFR) AF: 0.00591 AC: 195 AN: 33012

American (AMR) AF: 0.000291 AC: 13 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1091946

Other (OTH) AF: 0.000503 AC: 30 AN: 59650

GnomAD4 genome AF: 0.00164 AC: 249 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74440

African (AFR) AF: 0.00542 AC: 225 AN: 41536

American (AMR) AF: 0.00144 AC: 22 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00200

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cernunnos-XLF deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.2
DANN	Benign	0.80
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.060		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: rs150521220; hg19: chr2-219942093;