chr11-5234514-T-C

Variant names:

• chr11-5234514-T-C
• rs35518301
• ENST00000429817.1:c.-81A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.647
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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.: 32

GnomAD4 exome AF: 0.00000344 AC: 3 AN: 871646 Hom.: 0 Cov.: 12 AF XY: 0.00000655 AC XY: 3 AN XY: 457772

African (AFR) AF: 0.00 AC: 0 AN: 22252

American (AMR) AF: 0.00 AC: 0 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22486

East Asian (EAS) AF: 0.00 AC: 0 AN: 36954

South Asian (SAS) AF: 0.00 AC: 0 AN: 73942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4346

European-Non Finnish (NFE) AF: 0.00000522 AC: 3 AN: 575022

Other (OTH) AF: 0.00 AC: 0 AN: 40890

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Delta-plus-thalassemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.86
PhyloP100		0.65
PromoterAI		-0.046	Neutral
Mutation Taster		=99/201	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs35518301; hg19: chr11-5255744;