11-5248356-A-AG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000559.3(HBG1):c.*2_*3insC 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. Variant has been reported in ClinVar as Benign (★).

• 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 criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 11-5248356-A-AG is Benign according to our data. Variant chr11-5248356-A-AG is described in ClinVar as [Benign]. Clinvar id is 3059280.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
HBG1	NM_000559.3	c.*2_*3insC		3_prime_UTR_variant	3/3	ENST00000330597.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBG1	ENST00000330597.5	c.*2_*3insC		3_prime_UTR_variant	3/3	1	NM_000559.3	P1
HBG1	ENST00000648735.1	n.1377_1378insC		non_coding_transcript_exon_variant	2/2

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

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

Gnomad4 AFR exome AF: 0.894

Gnomad4 AMR exome AF: 0.830

Gnomad4 ASJ exome AF: 0.833

Gnomad4 EAS exome AF: 0.870

Gnomad4 SAS exome AF: 0.813

Gnomad4 FIN exome AF: 0.704

Gnomad4 NFE exome AF: 0.783

Gnomad4 OTH exome AF: 0.807

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

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.850

Gnomad4 ASJ AF: 0.837

Gnomad4 EAS AF: 0.895

Gnomad4 SAS AF: 0.820

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.791

Gnomad4 OTH AF: 0.848

Alfa AF: 0.728 Hom.: 4892

Asia WGS AF: 0.860 AC: 2989 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HBG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs371890964; hg19: chr11-5269586;