Variant 11-5226761-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000518.5(HBB):c.131A>C(p.Glu44Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E44Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:3

Conservation

PhyloP100: 0.281

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:

HBB (HGNC:):

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2526932).

BP6

Variant 11-5226761-T-G is Benign according to our data. Variant chr11-5226761-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15173.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.131A>C	p.Glu44Ala	missense_variant	2/3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.131A>C	p.Glu44Ala	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jun 30, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 18, 2019

The Hb G-Galveston variant (HBB: c.131A>C; p.Glu44Ala, also known as Glu43Ala when numbered from the mature protein; rs35262412) has not been reported in association with clinical symptoms, either in a homozygous state or when found with other pathogenic beta globin variants (Edington 1955, McCurdy 1974, Michlitsch 2009, HbVar and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), but it is reported in ClinVar (Variation ID: 15173). The glutamate at codon 44 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on available information, the Hb G-Galveston variant is considered likely benign. References: Link to HbVar for Hb G-Galveston: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=317 Edington G et al. Characterization and genetics of haemoglobin G. Nature. 1955; 175(4463):850-1. McCurdy P et al. Hemoglobin S-G (S-D) syndrome. Am J Med. 1974; 57(4):665-70. Michlitsch J et al. Newborn screening for hemoglobinopathies in California. Pediatr Blood Cancer. 2009; 52(4):486-90. -

HEMOGLOBIN G (PORT ARTHUR)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

HEMOGLOBIN G (GALVESTON)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

HEMOGLOBIN G (TEXAS)

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

Benign

0.16

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

T;T;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.62

.;T;T;T

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.1

L;L;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.0

N;.;.;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

D;.;.;D

Sift4G

Benign

0.51

T;.;.;.

Polyphen

0.013

B;B;.;.

Vest4

0.52

MutPred

0.44

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.86

MPC

0.043

ClinPred

0.10

GERP RS

1.6

Varity_R

0.29

gMVP

0.80

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