rs34878913

Variant names:

• chr11-5254482-A-G
• rs34878913
• NM_000184.3:c.125T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000184.3(HBG2):​c.125T>C​(p.Phe42Ser) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.50
• Publications: 4 publications found

Genes affected

HBG2 (HGNC:4832): (hemoglobin subunit gamma 2) 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]

HBG2 Gene-Disease associations (from GenCC):

• hemoglobinopathy Toms River

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cyanosis, transient neonatal

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000284931 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.125T>C	p.Phe42Ser	missense_variant	Exon 2 of 3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.125T>C	p.Phe42Ser	missense_variant	Exon 2 of 3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.125T>C	p.Phe42Ser	missense_variant	Exon 2 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1428T>C		non_coding_transcript_exon_variant	Exon 8 of 8	5		ENSP00000369609.3
ENSG00000239920	ENST00000380259.7	n.*1428T>C		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cyanosis, transient neonatal Pathogenic:1

May 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Jan 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with unexplained cyanosis that resolved in infancy (PMID: 7741137); Also known as p.Phe41Ser and hemoglobin F-Cincinnati; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7741137) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.5	.;.;H
PhyloP100		3.5
PROVEAN	Pathogenic	-6.3	.;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0010	.;.;D
Polyphen		1.0	.;.;D
Vest4		0.91
MutPred		0.91		Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);
MVP		0.99
ClinPred		0.99	D
GERP RS		2.7
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.86
gMVP		0.88
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs34878913; hg19: chr11-5275712;