rs142150013

Variant names:

• chr1-154273489-A-T
• rs142150013
• NM_006118.4:c.207A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006118.4(HAX1):​c.207A>T​(p.Pro69Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,614,168 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: HAX1 NM_006118.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.17
• Publications: 1 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=-0.92).
• BP6: Variant 1-154273489-A-T is Benign according to our data. Variant chr1-154273489-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00213 (325/152290) while in subpopulation NFE AF = 0.0029 (197/68020). AF 95% confidence interval is 0.00256. There are 1 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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.207A>T	p.Pro69Pro	synonymous	Exon 2 of 7	NP_006109.2
	HAX1	NM_001018837.2		c.63A>T	p.Pro21Pro	synonymous	Exon 2 of 7	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.207A>T	p.Pro69Pro	synonymous	Exon 2 of 7	ENSP00000329002.7	O00165-1
	HAX1	ENST00000457918.6	TSL:1	c.63A>T	p.Pro21Pro	synonymous	Exon 2 of 7	ENSP00000411448.2	O00165-5
	HAX1	ENST00000483970.7	TSL:2	c.207A>T	p.Pro69Pro	synonymous	Exon 2 of 7	ENSP00000435088.1	O00165-2

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152172 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00970

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00253 AC: 635 AN: 251476 AF XY: 0.00252

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00868

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00242 AC: 3534 AN: 1461878 Hom.: 9 Cov.: 33 AF XY: 0.00235 AC XY: 1711 AN XY: 727240

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00859 AC: 459 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00263 AC: 2927 AN: 1111996

Other (OTH) AF: 0.00176 AC: 106 AN: 60396

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152290 Hom.: 1 Cov.: 31 AF XY: 0.00224 AC XY: 167 AN XY: 74478

African (AFR) AF: 0.000385 AC: 16 AN: 41556

American (AMR) AF: 0.000457 AC: 7 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00970 AC: 103 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68020

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00215 Hom.: 0

Bravo AF: 0.00125

EpiCase AF: 0.00207

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	Kostmann syndrome (4)
-	-	1	HAX1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.7
DANN	Benign	0.80
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism

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: rs142150013; hg19: chr1-154245965;