rs549964658

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 8P and 3B. PP5_Very_StrongBP4BS1_SupportingBS2_Supporting

The ENST00000643122.1(HBD):c.-28-90C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 788,802 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00077 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 35 hom. )

Consequence

HBD
ENST00000643122.1 intron

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.942

Variant links:

Genes affected

HBD (HGNC:4829): (hemoglobin subunit delta) The delta (HBD) and beta (HBB) genes are normally expressed in the adult: two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin. Two alpha chains plus two delta chains constitute HbA-2, which with HbF comprises the remaining 3% of adult hemoglobin. Five beta-like globin genes are found within a 45 kb cluster on chromosome 11 in the following order: 5'-epsilon--Ggamma--Agamma--delta--beta-3'. Mutations in the delta-globin gene are associated with beta-thalassemia. [provided by RefSeq, Jul 2008]

HBD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PP5

Variant 11-5234551-G-A is Pathogenic according to our data. Variant chr11-5234551-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1163920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000768 (117/152290) while in subpopulation SAS AF= 0.0234 (113/4824). AF 95% confidence interval is 0.0199. There are 1 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 35 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4 link	c.-118C>T		upstream_gene_variant		ENST00000650601.1	NP_000510.1	P02042A0N071

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1 link	c.-118C>T		upstream_gene_variant			NM_000519.4	ENSP00000497529.1		P02042

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00288

AC:

1835

AN:

636512

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

1420

AN XY:

343226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000564

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000288

Gnomad4 SAS exome

AF:

0.0266

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.00153

GnomAD4 genome

AF:

0.000768

AC:

117

AN:

152290

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0234

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000185

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM1, PM2, PP3 -

Delta-beta-thalassemia

Pathogenic:1

May 06, 2024

MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant rs549964658, present in the 2KB_upstream of HBD gene. The variant has been identified as beta thalassemia carrier. In this case, the person having this variant is the father of Index case of Thalassemia, having HbA2 level of 2.8%( bellow 3.5%) . Though he also posses thalassemia career [ mutation of IVS 1-5 (G>C) ] masking the level of A2 for the presence of this delta mutation. For this ambiguous HPLC profile, we did target NGS of entire Bet globin gene cluster and found this delta mutation present along the other beta mutation IVS 1-5 (G>C) ]. Further clinical investigation,shows the person having Hb level 11.7g/dl which confirm the anemia state. -

HBD-related disorder

Pathogenic:1

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBD c.-118C>T variant is located in the 5' untranslated region. This variant, also referred to as c.-68C>T, has been reported in multiple individuals with delta-thalassemia (Table 1, Bouva et al. 2006. PubMed ID: 16434382; Alkindi et al. 2014. PubMed ID: 25043855; Table 2, Hanart et al. 2023. PubMed ID: 37276945). This variant is reported in one allele out of ~31,000 alleles in gnomAD. An in vitro experimental study suggests this variant reduces the expression of HBD protein (Figure 1, Alsultan et al. 2012. PubMed ID: 22641479). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1163920/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over