rs34220980

chr16-176717-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000558.5(HBA1):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000263 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000096 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000558.5 (HBA1) was described as [Likely_pathogenic] in ClinVar as 2573442
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-176717-A-G is Pathogenic according to our data. Variant chr16-176717-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2428673.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5	c.1A>G	p.Met1?	start_lost	1/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA1	ENST00000320868.9	c.1A>G	p.Met1?	start_lost	1/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1	n.20A>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000397797.1	c.-47A>G		5_prime_UTR_variant	1/3	2
HBA1	ENST00000487791.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000963 AC: 14 AN: 1454214 Hom.: 0 Cov.: 31 AF XY: 0.00000968 AC XY: 7 AN XY: 722990

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000704

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 29 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 21, 2022

The HBA1 c.1A>G; p.Met1? variant (rs34220980, HbVar ID: 1063), also known as alpha1 NcoI, is reported heterozygous in the literature in individuals with hypochromia and variable microcytosis (see Hbvar and references therein, Desogus 2015). Further, this variant has been observed in trans with double and single alpha globin gene deletions in individuals with Hb H disease and alpha thalassemia trait respectively (HbVar, Desogus 2015). This variant disrupts the translation initiation codon, resulting in reduced alpha globin protein. This variant is found in the African population with an allele frequency of 0.2% (4/22010 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Desogus MF et al. Investigating the alpha1(NcoI) mutation. Acta Haematol. 2015;133(2):145-7. PMID: 25247841. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MutPred		1.0		Loss of MoRF binding (P = 0.0883);
MVP		1.0
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.93
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34220980; hg19: chr16-226716;