11-5233076-A-G

Variant names:

• chr11-5233076-A-G
• rs759832815
• NM_000519.4:c.332T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000519.4(HBD):​c.332T>C​(p.Leu111Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.332T>C	p.Leu111Pro	missense_variant	Exon 3 of 3	ENST00000650601.1	NP_000510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBD	ENST00000650601.1	c.332T>C	p.Leu111Pro	missense_variant	Exon 3 of 3		NM_000519.4	ENSP00000497529.1
HBD	ENST00000643122.1	c.332T>C	p.Leu111Pro	missense_variant	Exon 4 of 4			ENSP00000494708.1
HBD	ENST00000417377.1	c.109T>C	p.Trp37Arg	missense_variant	Exon 2 of 2	3		ENSP00000414741.1
HBD	ENST00000292901.7	c.316-278T>C		intron_variant	Intron 2 of 2	3		ENSP00000292901.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thalassemia Uncertain:1

Jan 23, 2023

MVZ Dr. Eberhard & Partner Dortmund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was absent from variant databases and only found in 1 of 121292 alleles in ExAC. Computational evidence supports a rather deleterious effect on the gene or gene product (REVEL score 0,72 but discrepant predictions for splicing effects). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.021
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.47	.;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.9	H;H;H
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.3	.;D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0010	.;D;.
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.70		Loss of stability (P = 0.0971);Loss of stability (P = 0.0971);Loss of stability (P = 0.0971);
MVP		0.96
MPC		0.089
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs759832815; hg19: chr11-5254306;