11-5226561-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.19

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 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/exons	MANE	UniProt
HBB	NM_000518.5	c.315+16G>C		intron_variant		ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.315+16G>C		intron_variant		1	NM_000518.5	P1

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124382 AN: 151986 Hom.: 51464 Cov.: 31

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

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.: 33 AF XY: 0.813 AC XY: 589689 AN XY: 725362

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.: 31 AF XY: 0.810 AC XY: 60198 AN XY: 74346

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	research	College of Science, Al Muthanna University, Al Muthanna University	Jan 01, 2018	- -
Benign, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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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	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	9.3e-7	T
MutationTaster	Benign	1.0	P
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

Other links and lift over

dbSNP: rs10768683; hg19: chr11-5247791;