Genetic Variant HBA1:p.Asp75His (chr16-177056-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_StrongBP6

The NM_000558.5(HBA1):c.223G>C(p.Asp75His) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D75A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1O:6

Conservation

PhyloP100: 7.27

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

BP6

Variant 16-177056-G-C is Benign according to our data. Variant chr16-177056-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15733.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.223G>C	p.Asp75His	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA1	ENST00000320868.9 link	c.223G>C	p.Asp75His	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1 link	n.359G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA1	ENST00000487791.1 link	n.192G>C		non_coding_transcript_exon_variant	Exon 2 of 2	1
HBA1	ENST00000397797.1 link	c.127G>C	p.Asp43His	missense_variant	Exon 2 of 3	2		ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1Other:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 12, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA1 c.223G>C (p.Asp75His) variant (also known as Hb Q-Thailand) has been reported as having normal oxygen affinity and stability. In the published literature, the variant has been reported to be associated with mild thalassemic features and in a case of beta-thalassemia, and tends to occur with deletion of other alpha-globin genes (PMIDs: 2882671 (1987), 1487419 (1992), 29484903 (2018), 32995874 (2021), and 33593224 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Q-Thailand variant (HBA1: c.223G>C; p.Asp75His, also known as Asp74His when numbered from the mature protein, rs28928875, HbVar ID: 107) is reported in the literature, always in-cis with the 4.2kb deletion of HBA2, in multiple individuals affected with Hb Q-H disease, which resembles Hb H disease (Higgs 1980, Lie-Injo 1979, Lorkin 1970, Molchanova 1994, Singsanan 2010, Vella 1958). The Hb Q-Thailand variant is considered a stable hemoglobin variant (HbVar database and references therein). This variant is reported in ClinVar (Variation ID: 15733), and 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: 0.753). Based on available information, the Hb Q-Thailand variant is considered likely benign, though it indicates the presence of the 4.2kb alpha globin deletion in cis. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Higgs D et al. The genetic basis of Hb Q-H disease. Br J Haematol. 1980 46(3):387-400. PMID: 7448125. Lie-Injo L et al. The alpha-globin gene adjacent to the gene for HbQ-alpha 74 Asp replaced by His is deleted, but not that adjacent to the gene for HbG-alpha 30 Glu replaced by Gln; three-fourths of the alpha-globin genes are deleted in HbQ-alpha-thalassemia. Blood. 1979 54(6):1407-16. PMID: 508945. Lorkin P et al. Two haemoglobins Q, alpha-74 (EF3) and alpha-75 (EF4) aspartic acid to histidine. Br J Haematol. 1970 19(1):117-25. PMID: 5460202. Molchanova T et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 88(2):300-6. PMID: 7803274. Singsanan S et al. Hemoglobin Q-Thailand related disorders: origin, molecular, hematological and diagnostic aspects. Blood Cells Mol Dis. 2010 Oct 15;45(3):210-4. PMID: 20615730. Vella F et al. A haemoglobinopathy involving haemoglobin H and a new (Q) haemoglobin. Br Med J. 1958 1(5073):752-5. PMID: 13510789. -

alpha Thalassemia

Pathogenic:1

Dec 29, 2016

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN Q

Other:1

May 10, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN ASABARA

Other:1

May 10, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN Q (THAILAND)

Other:1

May 10, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN G (TAICHUNG)

Other:1

May 10, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN MAHIDOL

Other:1

May 10, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN KURASHIKI

Other:1

May 10, 2018

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

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.78

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.93

MutPred

0.97

Gain of catalytic residue at M77 (P = 0.0714);.;

MVP

1.0

ClinPred

1.0

GERP RS

3.3

Varity_R

0.88

gMVP

0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over