11-5226561-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000485743.1(HBB):c.331G>C(p.Ala111Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 1,609,510 control chromosomes in the GnomAD database, including 542,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/8 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A111S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.82 ( 51514 hom., cov: 31)

Exomes 𝑓: 0.82 ( 491164 hom. )

Consequence

HBB
ENST00000485743.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.3192546E-7).

BP6

Variant 11-5226561-C-G is Benign according to our data. Variant chr11-5226561-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226561-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.315+16G>C		intron_variant	Intron 2 of 2	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.315+16G>C		intron_variant	Intron 2 of 2	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.818

AC:

124382

AN:

151986

Hom.:

51464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.874

Gnomad AMI

AF:

0.971

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.865

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.645

Gnomad FIN

AF:

0.787

Gnomad MID

AF:

0.870

Gnomad NFE

AF:

0.841

Gnomad OTH

AF:

0.824

GnomAD3 exomes

AF:

0.765

AC:

192152

AN:

251156

Hom.:

75168

AF XY:

0.765

AC XY:

103897

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.874

Gnomad AMR exome

AF:

0.659

Gnomad ASJ exome

AF:

0.867

Gnomad EAS exome

AF:

0.502

Gnomad SAS exome

AF:

0.650

Gnomad FIN exome

AF:

0.790

Gnomad NFE exome

AF:

0.840

Gnomad OTH exome

AF:

0.797

GnomAD4 exome

AF:

0.817

AC:

1190789

AN:

1457406

Hom.:

491164

Cov.:

AF XY:

0.813

AC XY:

589689

AN XY:

725362

show subpopulations

Gnomad4 AFR exome

AF:

0.881

Gnomad4 AMR exome

AF:

0.668

Gnomad4 ASJ exome

AF:

0.863

Gnomad4 EAS exome

AF:

0.505

Gnomad4 SAS exome

AF:

0.660

Gnomad4 FIN exome

AF:

0.791

Gnomad4 NFE exome

AF:

0.845

Gnomad4 OTH exome

AF:

0.810

GnomAD4 genome

AF:

0.818

AC:

124491

AN:

152104

Hom.:

51514

Cov.:

AF XY:

0.810

AC XY:

60198

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.874

Gnomad4 AMR

AF:

0.728

Gnomad4 ASJ

AF:

0.865

Gnomad4 EAS

AF:

0.495

Gnomad4 SAS

AF:

0.646

Gnomad4 FIN

AF:

0.787

Gnomad4 NFE

AF:

0.841

Gnomad4 OTH

AF:

0.821

Alfa

AF:

0.833

Hom.:

9322

Bravo

AF:

0.822

TwinsUK

AF:

0.843

AC:

3127

ALSPAC

AF:

0.839

AC:

3235

ESP6500AA

AF:

0.870

AC:

3831

ESP6500EA

AF:

0.841

AC:

7229

ExAC

AF:

0.769

AC:

93406

Asia WGS

AF:

0.588

AC:

2049

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Benign:5

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jan 01, 2018

College of Science, Al Muthanna University, Al Muthanna University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Benign:4

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.038

DANN

Benign

0.37

FATHMM_MKL

Benign

0.0077

LIST_S2

Benign

0.20

MetaRNN

Benign

9.3e-7

GERP RS

-6.3

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