11-5248235-A-T

Variant names:

• chr11-5248235-A-T
• rs2402330
• NM_000559.3:c.*124T>A

Variant summary

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

The NM_000559.3(HBG1):​c.*124T>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,327,264 control chromosomes in the GnomAD database, including 922 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 0.046 (495 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (427 hom.)
• Consequence: HBG1 NM_000559.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268
• Publications: 1 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	NM_000559.3	MANE Select	c.*124T>A		downstream_gene	N/A	NP_000550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.*124T>A		downstream_gene	N/A	ENSP00000327431.4
	ENSG00000284931	ENST00000642908.1		c.*124T>A		downstream_gene	N/A	ENSP00000495346.1
	ENSG00000284931	ENST00000647543.1		c.*124T>A		downstream_gene	N/A	ENSP00000496470.1

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7008 AN: 152182 Hom.: 496 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.00508 AC: 5964 AN: 1174964 Hom.: 427 Cov.: 15 AF XY: 0.00441 AC XY: 2616 AN XY: 593352

African (AFR) AF: 0.175 AC: 4664 AN: 26624

American (AMR) AF: 0.00806 AC: 304 AN: 37704

Ashkenazi Jewish (ASJ) AF: 0.00330 AC: 77 AN: 23362

East Asian (EAS) AF: 0.00 AC: 0 AN: 37126

South Asian (SAS) AF: 0.000226 AC: 17 AN: 75070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51002

Middle Eastern (MID) AF: 0.00706 AC: 36 AN: 5098

European-Non Finnish (NFE) AF: 0.000351 AC: 305 AN: 868518

Other (OTH) AF: 0.0111 AC: 561 AN: 50460

GnomAD4 genome AF: 0.0461 AC: 7015 AN: 152300 Hom.: 495 Cov.: 33 AF XY: 0.0444 AC XY: 3304 AN XY: 74474

African (AFR) AF: 0.161 AC: 6685 AN: 41530

American (AMR) AF: 0.0150 AC: 229 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68032

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

Alfa AF: 0.0376 Hom.: 44

Bravo AF: 0.0586

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.082
DANN	Benign	0.17
PhyloP100		-0.27
Mutation Taster		=98/2	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: rs2402330; hg19: chr11-5269465;