rs1553289863

Variant names:

• chr1-154275142-C-G
• rs1553289863
• NM_006118.4:c.557-12C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_006118.4(HAX1):​c.557-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HAX1 NM_006118.4 intron
• Scores: Splicing: ADA: 0.0003826
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.849
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Kostmann syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1292156).
• BP6: Variant 1-154275142-C-G is Benign according to our data. Variant chr1-154275142-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435394.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006118.4. 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
	HAX1	NM_006118.4	MANE Select	c.557-12C>G		intron	N/A	NP_006109.2
	HAX1	NM_001018837.2		c.413-12C>G		intron	N/A	NP_001018238.1	A0A0S2Z565

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAX1	ENST00000328703.12	TSL:1 MANE Select	c.557-12C>G		intron	N/A	ENSP00000329002.7	O00165-1
	HAX1	ENST00000457918.6	TSL:1	c.413-12C>G		intron	N/A	ENSP00000411448.2	O00165-5
	HAX1	ENST00000435087.2	TSL:3	c.557C>G	p.Ser186Cys	missense	Exon 5 of 7	ENSP00000394920.2	Q5VYD6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000211 AC: 3 AN: 1420910 Hom.: 0 Cov.: 26 AF XY: 0.00000282 AC XY: 2 AN XY: 709612

African (AFR) AF: 0.00 AC: 0 AN: 32708

American (AMR) AF: 0.0000448 AC: 2 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074586

Other (OTH) AF: 0.00 AC: 0 AN: 59056

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Kostmann syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.4
DANN	Uncertain	0.98
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.85
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.021
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
MutPred		0.34		Loss of disorder (P = 0.0127)
MVP		0.57
ClinPred		0.088	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.030		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: rs1553289863; hg19: chr1-154247618;