dbSNP rs3813727: HBD:c.-28-221T>C (chr11-5234682-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.778

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

delta-beta-thalassemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HBD links:

ENSG00000298932 (HGNC:):

ENSG00000298932 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4 link	c.-249T>C		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.-249T>C		upstream_gene_variant			NM_000519.4	ENSP00000497529.1		P02042

Frequencies

GnomAD3 genomes

AF:

0.422

AC:

64068

AN:

151876

Hom.:

14986

Cov.:

show subpopulations

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.:

AF XY:

0.495

AC XY:

100918

AN XY:

203960

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

4762

9524

14286

19048

23810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.422

AC:

64106

AN:

151994

Hom.:

14996

Cov.:

AF XY:

0.430

AC XY:

31943

AN XY:

74276

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1796

3592

5389

7185

8981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.453

Hom.:

10833

Bravo

AF:

0.423

Asia WGS

AF:

0.596

AC:

2073

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.70

(source)

DANN

Benign

0.75

PhyloP100

-0.78

PromoterAI

0.099

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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rs3813727

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over