rs34647752

Positions:

• chr11-5248439-C-A
• chr11-5248439-C-T
• chr11-5248439-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000559.3(HBG1):​c.364G>T​(p.Glu122*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HBG1 NM_000559.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03

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 Likely_benign. Variant got -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBG1	NM_000559.3	c.364G>T	p.Glu122*	stop_gained	3/3	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.364G>T	p.Glu122*	stop_gained	3/3	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.364G>T	p.Glu122*	stop_gained	3/3			ENSP00000495346.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251182 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461782 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000416

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.52
GERP RS		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs33963857; hg19: chr11-5269669; COSMIC: COSV100400543; COSMIC: COSV100400543;