11-5248113-T-A

Variant names:

• chr11-5248113-T-A
• rs916111
• NM_000559.3:c.*246A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000559.3(HBG1):​c.*246A>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 513,726 control chromosomes in the GnomAD database, including 60,838 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (15347 hom., cov: 33)
  • Exomes 𝑓: 0.49 (45491 hom.)
• Consequence: HBG1 NM_000559.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.689
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	NM_000559.3	MANE Select	c.*246A>T		downstream_gene	N/A	NP_000550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.*246A>T		downstream_gene	N/A	ENSP00000327431.4
	ENSG00000284931	ENST00000642908.1		c.*246A>T		downstream_gene	N/A	ENSP00000495346.1
	ENSG00000284931	ENST00000647543.1		c.*246A>T		downstream_gene	N/A	ENSP00000496470.1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64574 AN: 151906 Hom.: 15333 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.485

GnomAD4 exome AF: 0.492 AC: 178087 AN: 361702 Hom.: 45491 Cov.: 4 AF XY: 0.496 AC XY: 95877 AN XY: 193368

African (AFR) AF: 0.222 AC: 2270 AN: 10218

American (AMR) AF: 0.592 AC: 9298 AN: 15700

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 6495 AN: 10478

East Asian (EAS) AF: 0.729 AC: 16081 AN: 22046

South Asian (SAS) AF: 0.531 AC: 22698 AN: 42708

European-Finnish (FIN) AF: 0.464 AC: 9116 AN: 19662

Middle Eastern (MID) AF: 0.612 AC: 901 AN: 1472

European-Non Finnish (NFE) AF: 0.462 AC: 101325 AN: 219452

Other (OTH) AF: 0.496 AC: 9903 AN: 19966

GnomAD4 genome AF: 0.425 AC: 64628 AN: 152024 Hom.: 15347 Cov.: 33 AF XY: 0.432 AC XY: 32059 AN XY: 74284

African (AFR) AF: 0.222 AC: 9208 AN: 41466

American (AMR) AF: 0.571 AC: 8719 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2151 AN: 3466

East Asian (EAS) AF: 0.774 AC: 4006 AN: 5176

South Asian (SAS) AF: 0.537 AC: 2585 AN: 4818

European-Finnish (FIN) AF: 0.461 AC: 4850 AN: 10528

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31430 AN: 67978

Other (OTH) AF: 0.488 AC: 1030 AN: 2112

Alfa AF: 0.430 Hom.: 1838

Bravo AF: 0.422

Asia WGS AF: 0.594 AC: 2067 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.56
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

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: rs916111; hg19: chr11-5269343;