chr11-5232968-T-C

Variant names:

• chr11-5232968-T-C
• rs34149886
• NM_000519.4:c.440A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000519.4(HBD):​c.440A>G​(p.His147Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBD NM_000519.4 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.72
• Publications: 1 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBD	NM_000519.4	c.440A>G	p.His147Arg	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.440A>G	p.His147Arg	missense_variant	Exon 3 of 3		NM_000519.4	ENSP00000497529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN A(2) MONREALE Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		1.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.2	.;D;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		0.99	D;D;D
Vest4		0.50
MutPred		0.73		Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);
MVP		0.79
MPC		0.072
ClinPred		0.96	D
GERP RS		2.4
Varity_R		0.70
gMVP		0.39
Mutation Taster		=28/72	disease causing

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: rs34149886; hg19: chr11-5254198;