dbSNP rs35518301: HBD:c.-81A>G (chr11-5234514-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The ENST00000643122.1(HBD):c.-28-53A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 871,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HBD
ENST00000643122.1 intron

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.647

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5234514-T-C is Pathogenic according to our data. Variant chr11-5234514-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 15087.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBD	NM_000519.4	MANE Select	c.-81A>G		upstream_gene	N/A	NP_000510.1	P02042

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HBD	ENST00000429817.1	TSL:5	c.-81A>G	5_prime_UTR	Exon 2 of 3	ENSP00000393810.1	E9PEW8
HBD	ENST00000643122.1		c.-28-53A>G	intron	N/A	ENSP00000494708.1	P02042
ENSG00000298932	ENST00000759072.1		n.266-8595T>C	intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000344

AC:

AN:

871646

Hom.:

Cov.:

AF XY:

0.00000655

AC XY:

AN XY:

457772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22252

American (AMR)

AF:

0.00

AC:

AN:

43278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22486

East Asian (EAS)

AF:

0.00

AC:

AN:

36954

South Asian (SAS)

AF:

0.00

AC:

AN:

73942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4346

European-Non Finnish (NFE)

AF:

0.00000522

AC:

AN:

575022

Other (OTH)

AF:

0.00

AC:

AN:

40890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Delta-plus-thalassemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.65

PromoterAI

-0.046

Neutral

(source)

Mutation Taster

=99/201

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over