NM_000558.5:c.74A>G

Variant names:

• chr16-176790-A-G
• rs28928880
• NM_000558.5:c.74A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000558.5(HBA1):​c.74A>G​(p.Tyr25Cys) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y25H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.118

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.74A>G	p.Tyr25Cys	missense_variant	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.74A>G	p.Tyr25Cys	missense_variant	Exon 1 of 3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.93A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA1	ENST00000487791.1	n.43A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA1	ENST00000397797.1	c.-2+28A>G		intron_variant	Intron 1 of 2	2		ENSP00000380899.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000351 AC: 5 AN: 1425542 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 707866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000588

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBA1 c.74A>G (p.Tyr25Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-06 in 1568590 control chromosomes in the gnomAD database (v4.1 dataset)in the gnomAD database (v4.1 dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.74A>G (aka. Hb Ramona) has been reported in the literature as a hemoglobin variant with altered mobility on isoelectricfocusing, and was incidentally found in an asymptomatic heterozygote, who had no hematological abnormalities (Pobedimskay_1994). This report does not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 7852094). ClinVar contains an entry for this variant (Variation ID: 15860). Based on the evidence outlined above, the variant was classified as uncertain significance. -

HEMOGLOBIN RAMONA Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.067	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.051	T
Vest4		0.33
MutPred		0.86		Loss of phosphorylation at Y25 (P = 0.0368);
MVP		1.0
ClinPred		0.97	D
GERP RS		1.9
Varity_R		0.85
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs28928880; hg19: chr16-226789;