chr11-5249786-C-G

Variant names:

• chr11-5249786-C-G
• rs33924825
• NM_000559.3:c.19G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000559.3(HBG1):​c.19G>C​(p.Glu7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.45
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32361776).

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.19G>C	p.Glu7Gln	missense	Exon 1 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.19G>C	p.Glu7Gln	missense	Exon 1 of 3	ENSP00000327431.4	P69891
	ENSG00000284931	ENST00000642908.1		c.316-1299G>C		intron	N/A	ENSP00000495346.1	A0AA75LVZ2
	HBG1	ENST00000632727.1	TSL:3	c.19G>C	p.Glu7Gln	missense	Exon 1 of 3	ENSP00000488759.1	A0A0J9YYA3

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome AF: 0.00000329 AC: 1 AN: 303734 Hom.: 0 Cov.: 0 AF XY: 0.00000624 AC XY: 1 AN XY: 160330

African (AFR) AF: 0.00 AC: 0 AN: 8754

American (AMR) AF: 0.00 AC: 0 AN: 13956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9020

East Asian (EAS) AF: 0.00 AC: 0 AN: 18244

South Asian (SAS) AF: 0.00 AC: 0 AN: 36122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1202

European-Non Finnish (NFE) AF: 0.00000556 AC: 1 AN: 179824

Other (OTH) AF: 0.00 AC: 0 AN: 16770

GnomAD4 genome Cov.: 5

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Benign	0.95
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.51	D
PhyloP100		1.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.18
MutPred		0.51		Loss of ubiquitination at K9 (P = 0.0573)
MVP		0.93
MPC		1.9
ClinPred		0.80	D
GERP RS		2.8
PromoterAI		-0.0014	Neutral
gMVP		0.21
Mutation Taster		=30/70	disease causing

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: rs33924825; hg19: chr11-5271016;