rs179363870

chr1-154273878-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_Moderate 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. 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

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 Uncertain_significance. Variant got 5 ACMG points.

• PS1: Transcript NM_006118.4 (HAX1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAX1	NM_006118.4	c.421T>C	p.Phe141Leu	missense_variant	3/7	ENST00000328703.12
HAX1	NM_001018837.2	c.277T>C	p.Phe93Leu	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAX1	ENST00000328703.12	c.421T>C	p.Phe141Leu	missense_variant	3/7	1	NM_006118.4	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

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;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	0.76	N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.82	N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.90	P;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs179363870; hg19: chr1-154246354;