rs3759074

Variant names:

• chr11-5236548-G-A
• rs3759074
• ENST00000643122.1:c.-28-2087C>T

Variant summary

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

The ENST00000643122.1(HBD):​c.-28-2087C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,062 control chromosomes in the GnomAD database, including 4,527 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 0.23 (4527 hom., cov: 32)
• Consequence: HBD ENST00000643122.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.786
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000643122.1	c.-28-2087C>T		intron_variant	Intron 1 of 3			ENSP00000494708.1
ENSG00000298932	ENST00000759072.1	n.266-6561G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34706 AN: 151944 Hom.: 4530 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.230

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34708 AN: 152062 Hom.: 4527 Cov.: 32 AF XY: 0.223 AC XY: 16563 AN XY: 74342

African (AFR) AF: 0.132 AC: 5463 AN: 41468

American (AMR) AF: 0.198 AC: 3031 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 571 AN: 3472

East Asian (EAS) AF: 0.115 AC: 594 AN: 5172

South Asian (SAS) AF: 0.264 AC: 1274 AN: 4824

European-Finnish (FIN) AF: 0.207 AC: 2193 AN: 10578

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20822 AN: 67962

Other (OTH) AF: 0.231 AC: 487 AN: 2108

Alfa AF: 0.257 Hom.: 869

Bravo AF: 0.220

Asia WGS AF: 0.227 AC: 788 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.54
DANN	Benign	0.46
PhyloP100		-0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3759074; hg19: chr11-5257778; COSMIC: COSV53083487; COSMIC: COSV53083487;