16-176762-G-C

Variant names:

• chr16-176762-G-C
• rs35816645
• NM_000558.5:c.46G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_000558.5(HBA1):​c.46G>C​(p.Gly16Arg) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency: Genomes: not found (cov: 28)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:2
• Conservation: PhyloP100: -0.533

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• BP6: Variant 16-176762-G-C is Benign according to our data. Variant chr16-176762-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 15797.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.46G>C	p.Gly16Arg	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.46G>C	p.Gly16Arg	missense_variant	Exon 1 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 28

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Siam/Hb Ottawa variant (HBA1/HBA2: c.46G>C; p.Gly16Arg), also known as Gly15Arg when numbered from the mature protein, rs35816645, HbVar ID:18, ClinVar Variation ID: 15797) is reported in the heterozygous state in individuals with no clinical features with normal hematology (Huang 2011, Lou 2014, Yodsowan 2000), or whose hematological abnormality is attributed to another genetic cause (Zhao 2021). Abnormal electrophoresis results have been described for this variant (Hb Var Database). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.590). 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 Huang Y et al. Molecular and clinical characteristics of hemoglobin Ottawa detected in a Chinese population. Mol Med Rep. 2011 May-Jun;4(3):581-3. PMID: 21468611. Lou JW et al. Prevalence and molecular characterization of structural hemoglobin variants in the Dongguan region of Guangdong province, southern China. Hemoglobin. 2014;38(4):282-6. PMID: 24985555. Yodsowan B et al. Hb Siam (alpha15(A13)Gly-->Arg) is a GGT-->CGT mutation in the alpha1-globin gene. Hemoglobin. 2000 Feb;24(1):71-5. PMID: 10722119. Zhao RQ et al. A novel SPTB frameshift deletion causing hereditary spherocytosis identified by next-generation sequencing in a Chinese family. Int J Lab Hematol. 2021 Dec;43(6):e294-e297. PMID: 33974364. -

HEMOGLOBIN OTTAWA Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN SIAM 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	0.41
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.26	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.021	D
Sift4G	Benign	0.10	T
Vest4		0.77
MutPred		0.47		Gain of MoRF binding (P = 0.0113);
MVP		0.97
ClinPred		0.050	T
GERP RS		-3.0
Varity_R		0.40
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35816645; hg19: chr16-226761;