chr11-5225653-G-T

Position:

• chr11-5225653-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000518.5(HBB):​c.389C>A​(p.Ala130Asp) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A130P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: other no assertion criteria provided O:2
• Conservation: PhyloP100: 3.56

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225654-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.389C>A	p.Ala130Asp	missense_variant	3/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.389C>A	p.Ala130Asp	missense_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1	c.389C>A	p.Ala130Asp	missense_variant	3/3			ENSP00000494175	P1
HBB	ENST00000633227.1	c.*205C>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004
HBB	ENST00000475226.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: other

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN J (TAICHUNG) Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

HEMOGLOBIN K (CAMEROON) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	.;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.013	D;.
Polyphen		0.35	B;B
Vest4		0.73
MutPred		0.55		Gain of phosphorylation at Y131 (P = 0.0823);Gain of phosphorylation at Y131 (P = 0.0823);
MVP		0.91
MPC		0.046
ClinPred		0.96	D
GERP RS		2.8
Varity_R		0.74
gMVP		0.99

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: rs111645889; hg19: chr11-5246883;