11-5225620-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000518.5(HBB):c.422C>A(p.Ala141Asp) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A141T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: 5.81

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225620-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15545.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.422C>A	p.Ala141Asp	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.422C>A	p.Ala141Asp	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.422C>A	p.Ala141Asp	missense_variant	3/3			P1
HBB	ENST00000633227.1	c.*238C>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
HBB	ENST00000475226.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2018

The HBB c.422C>A; Ala140Asp variant (rs33927093), also known as Hb Himeji, has been reported in the heterozygous state in individuals with no clinical symptoms (HbVar database and references therein). However, its phenotype when found with other pathogenic globin variants is unknown, and the reported percentage of Hb X by hemoglobin electrophoresis in the presence of Hb Himeji ranges from 21-44% (HbVar database, Martins 1989, Ohba 1986), so this structural variant may be unstable. This variant is listed in ClinVar (Variation ID: 15197), but is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at residue 140 is highly conserved, and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.421G>A, p.Ala140Thr, Hb Saint-Jacques; c.422C>T, p.Ala140Val, Hb Puttelange) have been reported the heterozygous state in individuals with erythrocytosis (HbVar database and references therein). Due to limited information, the clinical significance of the Hb Himeji variant is uncertain at this time. References: Link to HbVar database for Hb Himeji: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=556 Link to HbVar database for Hb Saint-Jacques: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=555&.cgifields=histD Link to HbVar database for Hb Puttelange: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=557&.cgifields=histD Martins MC et al. Hb Himeji or alpha 2 beta 2(140)(H18)Ala----Asp in a Portuguese family. Hemoglobin. 1989;13(4):411-5. Ohba Y et al. Hb Himeji or beta 140 (H18) Ala----Asp. A slightly unstable hemoglobin with increased beta N-terminal glycation. Hemoglobin. 1986;10(2):109-25. -

beta Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

HEMOGLOBIN HIMEJI Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.85		Loss of MoRF binding (P = 0.0659);Loss of MoRF binding (P = 0.0659);
MVP		0.94
MPC		0.29
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.84
gMVP		0.98

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: rs33927093; hg19: chr11-5246850;