Variant 11-5226615-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The ENST00000335295.4(HBB):c.277C>T(p.His93Tyr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H93?) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

HBB
ENST00000335295.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:3

Conservation

PhyloP100: 7.51

Variant links:

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]

HBB links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in ENST00000335295.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226613-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664746.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 11-5226615-G-A is Pathogenic according to our data. Variant chr11-5226615-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15255.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 linkuse as main transcript	c.277C>T	p.His93Tyr	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 linkuse as main transcript	c.277C>T	p.His93Tyr	missense_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 14, 2023

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in de novo heterozygous individuals (PMIDs: 1398295 (1992), 32747614 (2020)) and in families that have been described as generally asymptomatic, but also affected with cyanosis, methemoglobinemia, and hemolytic anemia especially during crises (PMIDs: 5669922 (1968), 933112 (1976), 31267164 (2019), 33251782 (2020)). Functional studies have shown that this variant is unstable (PMID: 933112 (1976)). Based on the available information, this variant is classified as pathogenic. -

METHEMOGLOBINEMIA, BETA TYPE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1998

- -

HEMOGLOBIN M (HYDE PARK)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN M (AKITA)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN M (MILWAUKEE 2)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.7

H;H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.7

D;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.95

MutPred

0.95

Loss of methylation at K96 (P = 0.0553);Loss of methylation at K96 (P = 0.0553);Loss of methylation at K96 (P = 0.0553);

MVP

0.88

MPC

0.27

ClinPred

1.0

GERP RS

5.2

Varity_R

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over