11-5248356-A-AG

Variant names:

• chr11-5248356-A-AG
• rs371890964
• NM_000559.3:c.*2dupC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000559.3(HBG1):​c.*2dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 151,530 control chromosomes in the GnomAD database, including 51,501 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (51501 hom., cov: 30)
  • Exomes 𝑓: 0.79 (453941 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 3_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.14
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3	c.*2dupC		3_prime_UTR_variant	Exon 3 of 3	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.*2dupC		3_prime_UTR_variant	Exon 3 of 3	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.*2dupC		3_prime_UTR_variant	Exon 3 of 3			ENSP00000495346.1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124525 AN: 151412 Hom.: 51443 Cov.: 30

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.895

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.846

GnomAD2 exomes AF: 0.649 AC: 154746 AN: 238422 AF XY: 0.646

Gnomad AFR exome AF: 0.705

Gnomad AMR exome AF: 0.717

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.825

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.655

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.790 AC: 1146820 AN: 1450844 Hom.: 453941 Cov.: 34 AF XY: 0.790 AC XY: 570627 AN XY: 722016

African (AFR) AF: 0.894 AC: 29778 AN: 33304

American (AMR) AF: 0.830 AC: 37070 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 21720 AN: 26074

East Asian (EAS) AF: 0.870 AC: 34516 AN: 39670

South Asian (SAS) AF: 0.813 AC: 69920 AN: 85976

European-Finnish (FIN) AF: 0.704 AC: 37581 AN: 53384

Middle Eastern (MID) AF: 0.857 AC: 4923 AN: 5746

European-Non Finnish (NFE) AF: 0.783 AC: 862853 AN: 1101996

Other (OTH) AF: 0.807 AC: 48459 AN: 60040

GnomAD4 genome AF: 0.823 AC: 124645 AN: 151530 Hom.: 51501 Cov.: 30 AF XY: 0.818 AC XY: 60540 AN XY: 74026

African (AFR) AF: 0.891 AC: 36846 AN: 41336

American (AMR) AF: 0.850 AC: 12950 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2893 AN: 3458

East Asian (EAS) AF: 0.895 AC: 4610 AN: 5150

South Asian (SAS) AF: 0.820 AC: 3953 AN: 4818

European-Finnish (FIN) AF: 0.677 AC: 7135 AN: 10534

Middle Eastern (MID) AF: 0.835 AC: 237 AN: 284

European-Non Finnish (NFE) AF: 0.791 AC: 53563 AN: 67710

Other (OTH) AF: 0.848 AC: 1784 AN: 2104

Alfa AF: 0.728 Hom.: 4892

Asia WGS AF: 0.860 AC: 2989 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HBG1-related disorder Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
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: rs371890964; hg19: chr11-5269586;