chr11-5249466-C-G

Variant names:

• chr11-5249466-C-G
• rs34049890
• NM_000559.3:c.217G>C

Variant summary

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

The NM_000559.3(HBG1):​c.217G>C​(p.Gly73Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 9)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.47
• 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 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	NM_000559.3	MANE Select	c.217G>C	p.Gly73Arg	missense	Exon 2 of 3	NP_000550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.217G>C	p.Gly73Arg	missense	Exon 2 of 3	ENSP00000327431.4	P69891
	ENSG00000284931	ENST00000642908.1		c.316-979G>C		intron	N/A	ENSP00000495346.1	A0AA75LVZ2
	HBG1	ENST00000632727.1	TSL:3	c.*86G>C		3_prime_UTR	Exon 2 of 3	ENSP00000488759.1	A0A0J9YYA3

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD4 exome AF: 0.00000373 AC: 3 AN: 804484 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 407426

African (AFR) AF: 0.00 AC: 0 AN: 18458

American (AMR) AF: 0.00 AC: 0 AN: 32908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18584

East Asian (EAS) AF: 0.0000957 AC: 3 AN: 31340

South Asian (SAS) AF: 0.00 AC: 0 AN: 57566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2962

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 566412

Other (OTH) AF: 0.00 AC: 0 AN: 36422

GnomAD4 genome Cov.: 9

ClinVar

ClinVar submissions as Germline

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	HEMOGLOBIN F (IWATA) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.043
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.44	D
PhyloP100		1.5
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.099	T
Polyphen		0.98	D
Vest4		0.24
MutPred		0.62		Gain of MoRF binding (P = 0.0106)
MVP		0.95
MPC		2.4
ClinPred		0.94	D
GERP RS		2.8
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.61
Mutation Taster		=32/68	disease causing

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: rs34049890; hg19: chr11-5270696;