16-176760-G-A

Variant names:

• chr16-176760-G-A
• rs63750090
• NM_000558.5:c.44G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000558.5(HBA1):​c.44G>A​(p.Trp15*) variant causes a stop gained 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.19
• Publications: 5 publications found

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

HBA1 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000294436 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 46 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-176760-G-A is Pathogenic according to our data. Variant chr16-176760-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3075902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.44G>A	p.Trp15*	stop_gained	Exon 1 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.44G>A	p.Trp15*	stop_gained	Exon 1 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.0000180 AC: 3 AN: 166914 AF XY: 0.0000335

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000626 AC: 9 AN: 1437434 Hom.: 0 Cov.: 27 AF XY: 0.0000112 AC XY: 8 AN XY: 713718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32468

American (AMR) AF: 0.00 AC: 0 AN: 41908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 38642

South Asian (SAS) AF: 0.000108 AC: 9 AN: 83002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4572

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100274

Other (OTH) AF: 0.00 AC: 0 AN: 59372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ExAC AF: 0.00000851 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia Pathogenic:1

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp15X variant in HBA1 has been reported in at least 1 individual with microcytosis who also carried the -3.7 deletion (Chow 2013 PMID: 24018802, Harteveld 2003 PMID: 14508795, https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2515). It has been reported in clinvar (Variation ID 811820) was absent from large population studies. This nonsense variant leads to a premature termination codon at position 15, which is predicted to lead to a truncated or absent protein. Loss of function of the HBA1 gene is an established disease mechanism in autosomal recessive Alpha Thalassaemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3. -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693798:Methemoglobinemia, alpha type;C4693823:Erythrocytosis, familial, 7 Pathogenic:1

Feb 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		3.2
Vest4		0.68
GERP RS		4.5
PromoterAI		0.033	Neutral
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs63750090; hg19: chr16-226759;