chr11-5226794-A-T

Position:

• chr11-5226794-A-T

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.98T>A​(p.Leu33Gln) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L33R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.70

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 (HGNC:):

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, 0.986
• PP5: Variant 11-5226794-A-T is Pathogenic according to our data. Variant chr11-5226794-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 478852.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5226794-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.98T>A	p.Leu33Gln	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.98T>A	p.Leu33Gln	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 19, 2020

The Hb Clermont Ferrand variant (HBB: c.98T>A; p.Leu33Gln, also known as Leu32Gln when numbered from the mature protein, rs33948578) is reported in an individual with mild hemolytic anemia (HbVar database). This variant has also been observed in cis to the Hb Koln variant (c.295G>A; p.Val99Met) in another individual with hemolytic anemia, a complex variant reported as Hb Medicine Lake (Coleman 1995). The p.Leu33Gln variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 33 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Leu33Arg, p.Leu33Pro) have been reported de novo in individuals with hemolytic anemia, and are considered disease-causing, unstable variants (Chang 2002, Walker 2003). Based on available information, the p.Leu33Gln variant is considered to be likely pathogenic. References: Link to Hb Clermont Ferrand in HbVar: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2542 Chang JG et al. Unstable Hb Perth in a Taiwanese subject: a T-->C substitution at codon 32 of the beta-globin gene creates an MspI site. Hemoglobin. 2002 Feb;26(1):91-4. Coleman MB et al. Two missense mutations in the beta-globin gene can cause severe beta thalassemia. Hemoglobin Medicine Lake (beta 32[B14]leucine-->glutamine; 98 [FG5] valine-->methionine). J Clin Invest. 1995 Feb;95(2):503-9. Walker L et al. Hb Castilla [beta32(B14)Leu --> Arg] caused by a de novo mutation. Hemoglobin. 2003 Nov;27(4):253-6. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.3	D;.;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.90		Loss of stability (P = 0.0749);Loss of stability (P = 0.0749);Loss of stability (P = 0.0749);Loss of stability (P = 0.0749);
MVP		0.97
MPC		0.26
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33948578; hg19: chr11-5248024;