1-154272666-T-G

Position:

• chr1-154272666-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006118.4(HAX1):​c.-58T>G 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 0.272 in 1,555,112 control chromosomes in the GnomAD database, including 62,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4605 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57508 hom.)
• Consequence: HAX1 NM_006118.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.10

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-154272666-T-G is Benign according to our data. Variant chr1-154272666-T-G is described in ClinVar as [Benign]. Clinvar id is 292700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAX1	NM_006118.4	c.-58T>G		5_prime_UTR_premature_start_codon_gain_variant	1/7	ENST00000328703.12	NP_006109.2
HAX1	NM_006118.4	c.-58T>G		5_prime_UTR_variant	1/7	ENST00000328703.12	NP_006109.2
HAX1	NM_001018837.2	c.-58T>G		5_prime_UTR_premature_start_codon_gain_variant	1/7		NP_001018238.1
HAX1	NM_001018837.2	c.-58T>G		5_prime_UTR_variant	1/7		NP_001018238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAX1	ENST00000328703	c.-58T>G		5_prime_UTR_premature_start_codon_gain_variant	1/7	1	NM_006118.4	ENSP00000329002.7
HAX1	ENST00000328703	c.-58T>G		5_prime_UTR_variant	1/7	1	NM_006118.4	ENSP00000329002.7

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33022 AN: 152052 Hom.: 4607 Cov.: 32

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.278 AC: 389967 AN: 1402942 Hom.: 57508 Cov.: 25 AF XY: 0.276 AC XY: 193347 AN XY: 701008

Gnomad4 AFR exome AF: 0.0436

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.380

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.266

GnomAD4 genome AF: 0.217 AC: 33011 AN: 152170 Hom.: 4605 Cov.: 32 AF XY: 0.219 AC XY: 16318 AN XY: 74390

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.215

Alfa AF: 0.256 Hom.: 5294

Bravo AF: 0.196

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kostmann syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.2
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11265425; hg19: chr1-154245142; COSMIC: COSV55171217; COSMIC: COSV55171217;