rs36062788

Variant names:

• chr16-177006-G-A
• rs36062788
• NM_000558.5:c.173G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000558.5(HBA1):​c.173G>A​(p.Gly58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000852 in 1,174,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: other no assertion criteria provided O:4
• Conservation: PhyloP100: -2.84
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 26 uncertain in NM_000558.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.173G>A	p.Gly58Asp	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.173G>A	p.Gly58Asp	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.52e-7 AC: 1 AN: 1174256 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 590232

African (AFR) AF: 0.00 AC: 0 AN: 27436

American (AMR) AF: 0.00 AC: 0 AN: 36556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23880

East Asian (EAS) AF: 0.00 AC: 0 AN: 35282

South Asian (SAS) AF: 0.00 AC: 0 AN: 77514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3656

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 884182

Other (OTH) AF: 0.00 AC: 0 AN: 50792

GnomAD4 genome Cov.: 31

ClinVar

Significance: other

Submissions summary: Other:4

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN J (NORFOLK) Other:1

Mar 10, 1984

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN KAGOSHIMA Other:1

Mar 10, 1984

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN NORFOLK Other:1

Mar 10, 1984

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN NISHIK Other:1

Mar 10, 1984

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	Benign	0.30
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	0.072
DANN	Benign	0.90
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	0.089	D
PhyloP100		-2.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.053	T;D
Vest4		0.55
MutPred		0.48		Loss of ubiquitination at K57 (P = 0.0795);.;
MVP		1.0
ClinPred		0.16	T
GERP RS		-4.3
PromoterAI		0.020	Neutral
Varity_R		0.52
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs36062788; hg19: chr16-227005;