11-5226594-C-A

Position:

• chr11-5226594-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):​c.298G>T​(p.Asp100Tyr) variant causes a missense change involving the alteration of a 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.35

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-5226594-C-A is Pathogenic according to our data. Variant chr11-5226594-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 15397.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.298G>T	p.Asp100Tyr	missense_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.298G>T	p.Asp100Tyr	missense_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Erythrocytosis, familial, 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.298G>Tp.Asp100Tyr in HBB gene has been reported to the ClinVar database as Pathogenic. The p.Asp100Tyr variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. The amino acid change p.Asp100Tyr in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 100 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance VUS. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1968	- -

HEMOGLOBIN YPSILANTI Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.9	D;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0030	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.93		Gain of methylation at K96 (P = 0.045);Gain of methylation at K96 (P = 0.045);Gain of methylation at K96 (P = 0.045);
MVP		0.96
MPC		0.28
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.98

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: rs33954595; hg19: chr11-5247824;