ENST00000643122.1:c.-28-221T>C

Variant names:

• chr11-5234682-A-G
• rs3813727
• ENST00000643122.1:c.-28-221T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000643122.1(HBD):​c.-28-221T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 534,640 control chromosomes in the GnomAD database, including 62,735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14996 hom., cov: 32)
  • Exomes 𝑓: 0.49 (47739 hom.)
• Consequence: HBD ENST00000643122.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.778
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-5234682-A-G is Benign according to our data. Variant chr11-5234682-A-G is described in ClinVar as Benign. ClinVar VariationId is 1236912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000643122.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	NM_000519.4	MANE Select	c.-249T>C		upstream_gene	N/A	NP_000510.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	ENST00000643122.1		c.-28-221T>C		intron	N/A	ENSP00000494708.1
	HBD	ENST00000429817.1	TSL:5	c.-97-152T>C		intron	N/A	ENSP00000393810.1
	ENSG00000298932	ENST00000759072.1		n.266-8427A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64068 AN: 151876 Hom.: 14986 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.479

GnomAD4 exome AF: 0.490 AC: 187472 AN: 382646 Hom.: 47739 Cov.: 0 AF XY: 0.495 AC XY: 100918 AN XY: 203960

African (AFR) AF: 0.246 AC: 2688 AN: 10926

American (AMR) AF: 0.593 AC: 10468 AN: 17646

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 7075 AN: 11556

East Asian (EAS) AF: 0.728 AC: 18083 AN: 24838

South Asian (SAS) AF: 0.541 AC: 24422 AN: 45122

European-Finnish (FIN) AF: 0.450 AC: 9924 AN: 22074

Middle Eastern (MID) AF: 0.613 AC: 993 AN: 1620

European-Non Finnish (NFE) AF: 0.454 AC: 102945 AN: 226984

Other (OTH) AF: 0.497 AC: 10874 AN: 21880

GnomAD4 genome AF: 0.422 AC: 64106 AN: 151994 Hom.: 14996 Cov.: 32 AF XY: 0.430 AC XY: 31943 AN XY: 74276

African (AFR) AF: 0.239 AC: 9920 AN: 41460

American (AMR) AF: 0.562 AC: 8590 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2142 AN: 3468

East Asian (EAS) AF: 0.781 AC: 4047 AN: 5184

South Asian (SAS) AF: 0.548 AC: 2641 AN: 4816

European-Finnish (FIN) AF: 0.446 AC: 4695 AN: 10538

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.448 AC: 30440 AN: 67940

Other (OTH) AF: 0.482 AC: 1016 AN: 2108

Alfa AF: 0.453 Hom.: 10833

Bravo AF: 0.423

Asia WGS AF: 0.596 AC: 2073 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.70
DANN	Benign	0.75
PhyloP100		-0.78
PromoterAI		0.099	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3813727; hg19: chr11-5255912;