rs179363870

Variant names:

• chr1-154273878-T-C
• rs179363870
• NM_006118.4:c.421T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006118.4(HAX1):​c.421T>C​(p.Phe141Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. F141F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HAX1 NM_006118.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.48
• Publications: 2 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAX1	NM_006118.4	MANE Select	c.421T>C	p.Phe141Leu	missense	Exon 3 of 7	NP_006109.2
	HAX1	NM_001018837.2		c.277T>C	p.Phe93Leu	missense	Exon 3 of 7	NP_001018238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAX1	ENST00000328703.12	TSL:1 MANE Select	c.421T>C	p.Phe141Leu	missense	Exon 3 of 7	ENSP00000329002.7
	HAX1	ENST00000457918.6	TSL:1	c.277T>C	p.Phe93Leu	missense	Exon 3 of 7	ENSP00000411448.2
	HAX1	ENST00000483970.7	TSL:2	c.445T>C	p.Phe149Leu	missense	Exon 3 of 7	ENSP00000435088.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.39
Sift	Benign	0.26	T
Sift4G	Benign	0.44	T
Polyphen		0.90	P
Vest4		0.63
MutPred		0.79		Loss of sheet (P = 0.0817)
MVP		0.91
MPC		0.32
ClinPred		0.45	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.35
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs179363870; hg19: chr1-154246354;