11-5248352-AG-A

Variant names:

• chr11-5248352-AG-A
• rs757054403
• NM_000559.3:c.*6delC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000559.3(HBG1):​c.*6delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.82 (51488 hom., cov: 0)
  • Exomes 𝑓: 0.79 (453083 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 3_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.07
• 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 -9 ACMG points.

• BP6: Variant 11-5248352-AG-A is Benign according to our data. Variant chr11-5248352-AG-A is described in ClinVar as [Benign]. Clinvar id is 3060285.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3	c.*6delC		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.*6delC		3_prime_UTR_variant	Exon 3 of 3	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.*6delC		3_prime_UTR_variant	Exon 3 of 3			ENSP00000495346.1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124501 AN: 151432 Hom.: 51431 Cov.: 0

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.894

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: 0.648 AC: 153826 AN: 237356 AF XY: 0.645

Gnomad AFR exome AF: 0.701

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.826

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.601

Gnomad OTH exome AF: 0.654

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.790 AC: 1145209 AN: 1449740 Hom.: 453083 Cov.: 0 AF XY: 0.790 AC XY: 569895 AN XY: 721520

African (AFR) AF: 0.894 AC: 29750 AN: 33286

American (AMR) AF: 0.830 AC: 37039 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 21712 AN: 26064

East Asian (EAS) AF: 0.870 AC: 34510 AN: 39662

South Asian (SAS) AF: 0.813 AC: 69892 AN: 85960

European-Finnish (FIN) AF: 0.704 AC: 37576 AN: 53384

Middle Eastern (MID) AF: 0.856 AC: 4914 AN: 5738

European-Non Finnish (NFE) AF: 0.782 AC: 861407 AN: 1101026

Other (OTH) AF: 0.807 AC: 48409 AN: 59996

GnomAD4 genome AF: 0.822 AC: 124619 AN: 151548 Hom.: 51488 Cov.: 0 AF XY: 0.818 AC XY: 60531 AN XY: 74044

African (AFR) AF: 0.891 AC: 36821 AN: 41324

American (AMR) AF: 0.850 AC: 12950 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2891 AN: 3456

East Asian (EAS) AF: 0.894 AC: 4606 AN: 5150

South Asian (SAS) AF: 0.820 AC: 3954 AN: 4820

European-Finnish (FIN) AF: 0.677 AC: 7140 AN: 10550

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

European-Non Finnish (NFE) AF: 0.791 AC: 53560 AN: 67718

Other (OTH) AF: 0.848 AC: 1786 AN: 2106

Alfa AF: 0.675 Hom.: 2881

Asia WGS AF: 0.859 AC: 2987 AN: 3478

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		-2.1
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: rs757054403; hg19: chr11-5269582;