rs13796

Positions:

• chr1-154273441-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006118.4(HAX1):​c.159T>C​(p.Ser53=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,614,000 control chromosomes in the GnomAD database, including 13,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (888 hom., cov: 31)
  • Exomes 𝑓: 0.13 (12565 hom.)
• Consequence: HAX1 NM_006118.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.348

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-154273441-T-C is Benign according to our data. Variant chr1-154273441-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 259917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154273441-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.348 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAX1	NM_006118.4	c.159T>C	p.Ser53=	synonymous_variant	2/7	ENST00000328703.12
HAX1	NM_001018837.2	c.54-39T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAX1	ENST00000328703.12	c.159T>C	p.Ser53=	synonymous_variant	2/7	1	NM_006118.4	P3

Frequencies

GnomAD3 genomes AF: 0.0962 AC: 14635 AN: 152062 Hom.: 889 Cov.: 31

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0660

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0833

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.116 AC: 29071 AN: 251372 Hom.: 1894 AF XY: 0.119 AC XY: 16112 AN XY: 135876

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.0720

Gnomad EAS exome AF: 0.0471

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.0847

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.127 AC: 186236 AN: 1461820 Hom.: 12565 Cov.: 34 AF XY: 0.128 AC XY: 93238 AN XY: 727210

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.0718

Gnomad4 EAS exome AF: 0.0289

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.0863

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.0962 AC: 14645 AN: 152180 Hom.: 888 Cov.: 31 AF XY: 0.0961 AC XY: 7153 AN XY: 74414

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0660

Gnomad4 EAS AF: 0.0400

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.0833

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.108

Alfa AF: 0.122 Hom.: 837

Bravo AF: 0.0937

Asia WGS AF: 0.0910 AC: 314 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kostmann syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hereditary insensitivity to pain with anhidrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

not provided Benign:1

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	-0.68
CADD	Benign	7.3
DANN	Benign	0.64

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: rs13796; hg19: chr1-154245917; COSMIC: COSV104377412; COSMIC: COSV104377412;