rs764082747

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting

The NM_006118.4(HAX1):c.91delG(p.Glu31LysfsTer54) variant causes a frameshift change. The variant allele was found at a frequency of 0.000482 in 1,613,368 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

HAX1
NM_006118.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.33

Variant links:

Genes affected

HAX1 (HGNC:16915): (HCLS1 associated protein X-1) The protein encoded by this gene is known to associate with hematopoietic cell-specific Lyn substrate 1, a substrate of Src family tyrosine kinases. It also interacts with the product of the polycystic kidney disease 2 gene, mutations in which are associated with autosomal-dominant polycystic kidney disease, and with the F-actin-binding protein, cortactin. It was earlier thought that this gene product is mainly localized in the mitochondria, however, recent studies indicate it to be localized in the cell body. Mutations in this gene result in autosomal recessive severe congenital neutropenia, also known as Kostmann disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HAX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-154273372-TG-T is Pathogenic according to our data. Variant chr1-154273372-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154273372-TG-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000506 (739/1461796) while in subpopulation NFE AF= 0.000643 (715/1111928). AF 95% confidence interval is 0.000603. There are 1 homozygotes in gnomad4_exome. There are 338 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAX1	NM_006118.4 link	c.91delG	p.Glu31LysfsTer54	frameshift_variant	Exon 2 of 7	ENST00000328703.12	NP_006109.2	O00165-1A0A0S2Z591
HAX1	NM_001018837.2 link	c.54-107delG		intron_variant	Intron 1 of 6		NP_001018238.1	O00165-5A0A0S2Z565

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAX1	ENST00000328703.12 link	c.91delG	p.Glu31LysfsTer54	frameshift_variant	Exon 2 of 7	1	NM_006118.4	ENSP00000329002.7		O00165-1

Frequencies

GnomAD3 genomes

AF:

0.000251

AC:

AN:

151572

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251294

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000379

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000506

AC:

739

AN:

1461796

Hom.:

Cov.:

AF XY:

0.000465

AC XY:

338

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000643

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000251

AC:

AN:

151572

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

AN XY:

73954

show subpopulations

Gnomad4 AFR

AF:

0.000219

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000383

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000219

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

May 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19036076, 34426522, 31589614, 32054657, 19499579) -

Dec 18, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2022

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_strong, PVS1 -

Mar 18, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kostmann syndrome

Pathogenic:6

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 19, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with severe congenital neutropenia 3 (MIM#610738). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 58 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with neutropenia and classified as pathogenic in ClinVar (PMID: 37193639). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu31Lysfs*54) in the HAX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HAX1 are known to be pathogenic (PMID: 17187068). This variant is present in population databases (rs764082747, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with severe congenital neutropenia (PMID: 19036076, 19499579). ClinVar contains an entry for this variant (Variation ID: 419887). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Severe congenital neutropenia

Pathogenic:1

Feb 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HAX1 c.91delG (p.Glu31LysfsX54) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00019 in 251294 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in HAX1 causing Severe Congenital Neutropenia (0.00019 vs 0.00079), allowing no conclusion about variant significance. c.91delG has been reported in the literature in individuals affected with Severe Congenital Neutropenia (e.g. Smith_2009, Carlsson_2012). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over