16-176937-T-G

Position:

• chr16-176937-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000558.5(HBA1):​c.104T>G​(p.Leu35Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:2
• Conservation: PhyloP100: -3.98

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5	c.104T>G	p.Leu35Arg	missense_variant	2/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.104T>G	p.Leu35Arg	missense_variant	2/3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.240T>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.73T>G		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.8T>G	p.Leu3Arg	missense_variant	2/3	2		ENSP00000380899.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000213 AC: 2 AN: 939048 Hom.: 0 Cov.: 13 AF XY: 0.00000416 AC XY: 2 AN XY: 481240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000292

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000234

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2022	The Hb Queens variant (HBA1: c.104T>G; p.Leu35Arg, also known as Leu34Arg when numbered from the mature protein, rs35203445) has been reported heterozygously in multiple individuals with no associated clinical symptoms (Lee 1992, Lin 2013, see HbVar database). However, it has been reported as mildly unstable (HbVar database), and its impact in the presence of pathogenic alpha globin variants is uncertain. This variant is reported in ClinVar (Variation ID: 15795) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 35 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.614). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Lee N et al. A family case of beta-thalassemia minor and hemoglobin Queens: alpha 34 (B15) Leu-Arg. J Korean Med Sci. 1992; 7(4):385-8. PMID: 1299245. Lin M et al. Molecular epidemiological survey of hemoglobinopathies in the Wuxi region of Jiangsu Province, eastern China. Hemoglobin. 2013; 37(5):454-66. PMID: 23806067. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 03, 2024	The HBA1 c.104T>G (p.Leu35Arg) variant, also known as Hb Queens, has been reported as a common variant in China (PMID: 31164695 (2019)). Individuals heterozygous for this variant are reported to have a normal clinical presentation (HbVar, http://globin.bx.psu.edu/). In addition, this variant is reported to have slightly increased oxygen affinity and is mildly unstable (PMID: 3446653 (1987) and HbVar, http://globin.bx.psu.edu/). In the published literature, the variant has been detected in individuals with no hematological symptoms except a mild anemia in some cases (PMIDs: 7096112 (1982), 3446653 (1987), 1299245 (1992), 23806067 (2013), and 24985555 (2014)). It has also been observed in an individual with microcytosis and borderline anemia however these clinical symptoms were possibly related to being also homozygous for Hb E (PMID: 7158628 (1982)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org.). Based on the available information, we are unable to determine the clinical significance of this variant. -

HEMOGLOBIN OGI Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

HEMOGLOBIN QUEENS Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.20	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.30	T;T
Vest4		0.54
MutPred		0.41		Gain of methylation at L35 (P = 0.0292);.;
MVP		0.90
ClinPred		0.18	T
GERP RS		-6.4
Varity_R		0.57
gMVP		0.83

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

Other links and lift over

dbSNP: rs35203445; hg19: chr16-226936;