1-154273441-T-C

Variant names:

• chr1-154273441-T-C
• rs13796
• NM_006118.4:c.159T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006118.4(HAX1):​c.159T>C​(p.Ser53Ser) 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:9
• Conservation: PhyloP100: -0.348
• Publications: 27 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 259917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.159T>C	p.Ser53Ser	synonymous	Exon 2 of 7	NP_006109.2
	HAX1	NM_001018837.2		c.54-39T>C		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.159T>C	p.Ser53Ser	synonymous	Exon 2 of 7	ENSP00000329002.7	O00165-1
	HAX1	ENST00000457918.6	TSL:1	c.54-39T>C		intron	N/A	ENSP00000411448.2	O00165-5
	HAX1	ENST00000483970.7	TSL:2	c.159T>C	p.Ser53Ser	synonymous	Exon 2 of 7	ENSP00000435088.1	O00165-2

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

GnomAD2 exomes AF: 0.116 AC: 29071 AN: 251372 AF XY: 0.119

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 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

African (AFR) AF: 0.0252 AC: 843 AN: 33480

American (AMR) AF: 0.123 AC: 5500 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 1876 AN: 26136

East Asian (EAS) AF: 0.0289 AC: 1146 AN: 39700

South Asian (SAS) AF: 0.148 AC: 12784 AN: 86256

European-Finnish (FIN) AF: 0.0863 AC: 4610 AN: 53418

Middle Eastern (MID) AF: 0.131 AC: 754 AN: 5768

European-Non Finnish (NFE) AF: 0.136 AC: 151587 AN: 1111952

Other (OTH) AF: 0.118 AC: 7136 AN: 60396

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

African (AFR) AF: 0.0300 AC: 1244 AN: 41528

American (AMR) AF: 0.101 AC: 1536 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 229 AN: 3470

East Asian (EAS) AF: 0.0400 AC: 207 AN: 5178

South Asian (SAS) AF: 0.142 AC: 683 AN: 4822

European-Finnish (FIN) AF: 0.0833 AC: 883 AN: 10600

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9416 AN: 67992

Other (OTH) AF: 0.108 AC: 228 AN: 2114

Alfa AF: 0.120 Hom.: 1101

Bravo AF: 0.0937

Asia WGS AF: 0.0910 AC: 314 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.135

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Kostmann syndrome (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary insensitivity to pain with anhidrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.3
DANN	Benign	0.64
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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