NM_000559.3:c.190C>T

Variant names:

• chr11-5249493-G-A
• NM_000559.3:c.190C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000559.3(HBG1):​c.190C>T​(p.His64Tyr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 9)
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

Genes affected

HBG1 (HGNC:4831): (hemoglobin subunit gamma 1) The gamma globin genes (HBG1 and HBG2) are normally expressed in the fetal liver, spleen and bone marrow. Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is normally replaced by adult hemoglobin (HbA) at birth. In some beta-thalassemias and related conditions, gamma chain production continues into adulthood. The two types of gamma chains differ at residue 136 where glycine is found in the G-gamma product (HBG2) and alanine is found in the A-gamma product (HBG1). The former is predominant at birth. The order of the genes in the beta-globin cluster is: 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ENSG00000284931 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site distal binding residue (size 0) in uniprot entity HBG1_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3	c.190C>T	p.His64Tyr	missense_variant	Exon 2 of 3	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.190C>T	p.His64Tyr	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.316-1006C>T		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary persistence of fetal hemoglobin Uncertain:1

Mar 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBG1 c.190C>T; p.His64Tyr variant, to our knowledge, is not reported in the medical literature or gene specific databases. However, another variant at this codon in the homologous HBG2 gene (Hb F-M-Osaka, HBG2: c.190C>T; p.His64Tyr, also known as His63Tyr when numbered from the mature protein, HbVar ID: 601) has been reported in newborns with mild methemoglobinemia and transient neonatal cyanosis (Alonso-Ojembarrena 2016, Chandran 2022, Chen 2024, Yuan 2020 see HbVar and references therein). Hb F-M-Osaka has also been found to segregate with transient neonatal cyanosis (Alonso-Ojembarrena 2016, Yuan 2020). HBG1 c.190C>T 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: 0.835). The HBG1 and HBG2 genes are highly homologous, differing at only one codon (Papachatzopoulou and Patrinos 2011). Based on the available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Alonso-Ojembarrena A et al. Hemoglobin M Disease as a Cause of Cyanosis in a Newborn. J Pediatr Hematol Oncol. 2016 Apr;38(3):173-5. PMID: 26694193. Chandran S et al. The journey from blue to pink–a rare cause for self-limiting methemoglobinemia in an Indian baby. Case Reports in Perinatal Medicine. 2022 Aug 11. https://doi.org/10.1515/crpm-2021-0054 Chen Y et al. Case Report: A case report and literature review of hemoglobin variation associated with neonatal cyanosis. Front Pediatr. 2024 Feb 13;12:1334757. PMID: 38415208. Papachatzopoulou A and Patrinos GP. Identical mutations in the paralogous human ?-globin genes leading to hemoglobin variants and nondeletional hereditary persistence of fetal hemoglobin. Hemoglobin. 2011;35(2):135-41. PMID: 21417570. Yuan J and Zhu XP. Clinical characteristics on manifestation and gene mutation of a transient neonatal cyanosis: A case report. World J Clin Cases. 2020 Jan 6;8(1):217-221. PMID: 31970190. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	0.014
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.54	P
Vest4		0.33
MutPred		0.96		Loss of disorder (P = 0.0349);
MVP		0.94
MPC		1.8
ClinPred		0.89	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-5270723;