chr11-5248569-A-C

Variant names:

• chr11-5248569-A-C
• rs28440105
• NM_000559.3:c.316-82T>G

Variant summary

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

The NM_000559.3(HBG1):​c.316-82T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 150,062 control chromosomes in the GnomAD database, including 50,217 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 0.82 (50217 hom., cov: 28)
  • Exomes 𝑓: 0.79 (347616 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 22 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 = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3	c.316-82T>G		intron_variant	Intron 2 of 2	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.316-82T>G		intron_variant	Intron 2 of 2	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.316-82T>G		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 122420 AN: 149948 Hom.: 50165 Cov.: 28

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.756

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.818

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.842

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.789 AC: 878099 AN: 1112438 Hom.: 347616 AF XY: 0.790 AC XY: 446984 AN XY: 565632

African (AFR) AF: 0.869 AC: 22091 AN: 25430

American (AMR) AF: 0.829 AC: 33214 AN: 40060

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 19478 AN: 23430

East Asian (EAS) AF: 0.867 AC: 31995 AN: 36918

South Asian (SAS) AF: 0.813 AC: 62467 AN: 76848

European-Finnish (FIN) AF: 0.703 AC: 36323 AN: 51642

Middle Eastern (MID) AF: 0.858 AC: 4151 AN: 4840

European-Non Finnish (NFE) AF: 0.782 AC: 629360 AN: 804932

Other (OTH) AF: 0.807 AC: 39020 AN: 48338

GnomAD4 genome AF: 0.817 AC: 122532 AN: 150062 Hom.: 50217 Cov.: 28 AF XY: 0.812 AC XY: 59572 AN XY: 73320

African (AFR) AF: 0.872 AC: 34760 AN: 39868

American (AMR) AF: 0.848 AC: 12877 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2885 AN: 3448

East Asian (EAS) AF: 0.894 AC: 4591 AN: 5136

South Asian (SAS) AF: 0.819 AC: 3919 AN: 4788

European-Finnish (FIN) AF: 0.677 AC: 7110 AN: 10504

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.792 AC: 53688 AN: 67828

Other (OTH) AF: 0.844 AC: 1769 AN: 2096

Alfa AF: 0.730 Hom.: 1980

Bravo AF: 0.832

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.6
DANN	Benign	0.72
PhyloP100		-0.54
Mutation Taster		=100/0	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: rs28440105; hg19: chr11-5269799;