11-5248439-C-G

Variant names:

• chr11-5248439-C-G
• rs33963857
• NM_000559.3:c.364G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000559.3(HBG1):​c.364G>C​(p.Glu122Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E122K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03
• Publications: 2 publications found

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]

HBG1 Gene-Disease associations (from GenCC):

• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284931 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3	c.364G>C	p.Glu122Gln	missense_variant	Exon 3 of 3	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.364G>C	p.Glu122Gln	missense_variant	Exon 3 of 3	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.364G>C	p.Glu122Gln	missense_variant	Exon 3 of 3			ENSP00000495346.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Benign	0.97
Eigen	Benign	0.018
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D;D;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.29	D
PhyloP100		3.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;.;.
Sift4G	Benign	0.096	T;.;.
Polyphen		0.98	D;.;.
Vest4		0.28
MutPred		0.62		Loss of ubiquitination at K121 (P = 0.1264);Loss of ubiquitination at K121 (P = 0.1264);.;
MVP		0.94
MPC		1.9
ClinPred		0.83	D
GERP RS		1.6
gMVP		0.45
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33963857; hg19: chr11-5269669;