chr2-219158323-C-T

Variant names:

• chr2-219158323-C-T
• rs34689457
• NM_024782.3:c.40G>A

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.40G>A​(p.Ala14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,614,152 control chromosomes in the GnomAD database, including 827 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A14V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.041 (440 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (387 hom.)
• Consequence: NHEJ1 NM_024782.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.16
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002818942).
• BP6: Variant 2-219158323-C-T is Benign according to our data. Variant chr2-219158323-C-T is described in ClinVar as Benign. ClinVar VariationId is 138520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	NM_024782.3	MANE Select	c.40G>A	p.Ala14Thr	missense	Exon 2 of 8	NP_079058.1	Q9H9Q4-1
	NHEJ1	NM_001377499.1		c.40G>A	p.Ala14Thr	missense	Exon 2 of 8	NP_001364428.1	H7C0G7
	NHEJ1	NM_001377498.1		c.40G>A	p.Ala14Thr	missense	Exon 2 of 8	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.40G>A	p.Ala14Thr	missense	Exon 2 of 8	ENSP00000349313.5	Q9H9Q4-1
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1162G>A		non_coding_transcript_exon	Exon 11 of 17	ENSP00000320919.3	F8W735
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1162G>A		3_prime_UTR	Exon 11 of 17	ENSP00000320919.3	F8W735

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6276 AN: 152146 Hom.: 440 Cov.: 31

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0110

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: 0.0392

GnomAD2 exomes AF: 0.0111 AC: 2790 AN: 251424 AF XY: 0.00828

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.00720

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00436 AC: 6368 AN: 1461888 Hom.: 387 Cov.: 33 AF XY: 0.00367 AC XY: 2672 AN XY: 727244

African (AFR) AF: 0.146 AC: 4889 AN: 33478

American (AMR) AF: 0.00796 AC: 356 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 345 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1112010

Other (OTH) AF: 0.00990 AC: 598 AN: 60396

GnomAD4 genome AF: 0.0413 AC: 6284 AN: 152264 Hom.: 440 Cov.: 31 AF XY: 0.0392 AC XY: 2916 AN XY: 74454

African (AFR) AF: 0.141 AC: 5848 AN: 41518

American (AMR) AF: 0.0183 AC: 280 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

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

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68028

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0131 Hom.: 380

Bravo AF: 0.0462

ESP6500AA AF: 0.125 AC: 552

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.0129 AC: 1561

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.11	T
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.18
MPC		0.31
ClinPred		0.021	T
GERP RS		4.8
PromoterAI		0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.12
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34689457; hg19: chr2-220023045; COSMIC: COSV99041314; COSMIC: COSV99041314;