NM_000558.5:c.418A>G

Variant names:

• chr16-177400-A-G
• rs33973086
• NM_000558.5:c.418A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PM1 PM2 PP3_Strong BP6_Moderate

The NM_000558.5(HBA1):​c.418A>G​(p.Lys140Glu) 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K140T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.43
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000558.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• BP6: Variant 16-177400-A-G is Benign according to our data. Variant chr16-177400-A-G is described in CliVar as Likely_benign. Clinvar id is 3766985.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-177400-A-G is described in CliVar as Likely_benign. Clinvar id is 3766985.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-177400-A-G is described in CliVar as Likely_benign. Clinvar id is 3766985.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-177400-A-G is described in CliVar as Likely_benign. Clinvar id is 3766985.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.418A>G	p.Lys140Glu	missense_variant	Exon 3 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.418A>G	p.Lys140Glu	missense_variant	Exon 3 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Hanamaki-2 variant (HBA1: c.418A>G; p.Lys140Glu, also known as Lys139Glu when numbered from the mature protein, rs33973086, HbVar ID: 1105) is reported in the heterozygous state in individuals with normal hematological parameters (see HbVar database, Orisaka 1992, Rahbar 1994). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.726), and functional studies demonstrate increased oxygen affinity (Orisaka 1992). Based on available information, this variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Orisaka M et al. A new alpha chain variant, Hb Hanamaki or alpha 2(139)(HC1)Lys----Glu beta 2, found in a Japanese family. Hemoglobin. 1992;16(1-2):67-71. PMID: 1634363. Rahbar S et al. A second case of Hb Hanamaki (alpha 2 139(HC1)Lys->Glu beta 2) in an American family with erythrocytosis. Hemoglobin. 1994 May;18(3):221-6. PMID: 7928378. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.33	D
PhyloP100		3.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0080	D;T
Vest4		0.71
MutPred		0.88		Loss of MoRF binding (P = 4e-04);.;
MVP		0.93
ClinPred		1.0	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.87
gMVP		0.93

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: rs33973086; hg19: chr16-227399;