NM_032492.4:c.-70G>C

Variant names:

• chr3-9890653-G-C
• rs279558
• NM_032492.4:c.-70G>C

Variant summary

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

The NM_032492.4(JAGN1):​c.-70G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,461,532 control chromosomes in the GnomAD database, including 335,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30760 hom., cov: 31)
  • Exomes 𝑓: 0.68 (304904 hom.)
• Consequence: JAGN1 NM_032492.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0610
• Publications: 9 publications found

Genes affected

JAGN1 (HGNC:26926): (jagunal homolog 1) The protein encoded by this gene is a transmembrane protein. It functions in the early secretory pathway and is necessary for neutrophil differentiation and survival. Mutations in this gene result in severe congenital neutropenia. [provided by RefSeq, Oct 2014]

JAGN1 Gene-Disease associations (from GenCC):

• autosomal recessive severe congenital neutropenia due to JAGN1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 3-9890653-G-C is Benign according to our data. Variant chr3-9890653-G-C is described in ClinVar as Benign. ClinVar VariationId is 1223060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032492.4. 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
	JAGN1	NM_032492.4	MANE Select	c.-70G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_115881.3
	JAGN1	NM_032492.4	MANE Select	c.-70G>C		5_prime_UTR	Exon 1 of 2	NP_115881.3
	JAGN1	NM_001363890.1		c.-338G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_001350819.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAGN1	ENST00000647897.1	MANE Select	c.-70G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000496942.1	Q8N5M9
	JAGN1	ENST00000647897.1	MANE Select	c.-70G>C		5_prime_UTR	Exon 1 of 2	ENSP00000496942.1	Q8N5M9
	JAGN1	ENST00000915552.1		c.-70G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000585611.1

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95753 AN: 151736 Hom.: 30740 Cov.: 31

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.681 AC: 891524 AN: 1309676 Hom.: 304904 Cov.: 18 AF XY: 0.681 AC XY: 440890 AN XY: 647582

African (AFR) AF: 0.494 AC: 14661 AN: 29678

American (AMR) AF: 0.602 AC: 20045 AN: 33324

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 15245 AN: 23480

East Asian (EAS) AF: 0.716 AC: 25531 AN: 35678

South Asian (SAS) AF: 0.651 AC: 49111 AN: 75484

European-Finnish (FIN) AF: 0.631 AC: 30966 AN: 49072

Middle Eastern (MID) AF: 0.676 AC: 3107 AN: 4596

European-Non Finnish (NFE) AF: 0.693 AC: 695759 AN: 1003676

Other (OTH) AF: 0.678 AC: 37099 AN: 54688

GnomAD4 genome AF: 0.631 AC: 95813 AN: 151856 Hom.: 30760 Cov.: 31 AF XY: 0.628 AC XY: 46614 AN XY: 74196

African (AFR) AF: 0.507 AC: 21000 AN: 41420

American (AMR) AF: 0.633 AC: 9673 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2269 AN: 3466

East Asian (EAS) AF: 0.710 AC: 3634 AN: 5116

South Asian (SAS) AF: 0.664 AC: 3194 AN: 4812

European-Finnish (FIN) AF: 0.631 AC: 6664 AN: 10566

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47098 AN: 67890

Other (OTH) AF: 0.649 AC: 1364 AN: 2102

Alfa AF: 0.571 Hom.: 1831

Bravo AF: 0.625

Asia WGS AF: 0.712 AC: 2472 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.2
DANN	Benign	0.65
PhyloP100		0.061
PromoterAI		-0.062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs279558; hg19: chr3-9932337; COSMIC: COSV57062656;