rs33922018

chr11-5226698-C-Gchr11-5226698-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000518.5(HBB):c.194G>C(p.Gly65Ala) 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. G65D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.50

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.194G>C	p.Gly65Ala	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.194G>C	p.Gly65Ala	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 08, 2019

The Hb Aubagne (HBB: c.194G>C; p.Gly65Ala, also known as Gly64Ala when numbered from the mature protein, rs33922018) variant is reported in the literature in the heterozygous state in a family with mild anemia and Heinz bodies and was considered mildly unstable (see link to HbVar; Lacan 2002). However, the effect when found with additional pathogenic HBB variants is unknown. Other variants at this codon (Hb J-Calabria, c.194G>A, p.Gly65Asp; Hb Calgary c.194G>T, p.Gly65Val; Hb Extremadura, c.[400G>C; 193G>A]; p.[Val134Leu; Gly65Ser]) have been reported in heterozygotes with mild anemia (Henderson 2016), and Hb J-Calabria has been reported with a second beta-thalassemia variant in an individual with chronic hemolytic anemia (see links to HbVar, Marinucci 1979). The Hb Aubagne variant is reported in ClinVar (Variation ID: 15599), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 65 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the Hb Aubagne variant is uncertain at this time. References: Link to HbVar for Hb Aubagne: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1143&.cgifields=histD Link to HbVar for Hb J-Calabria: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=362&.cgifields=histD Henderson SJ et al. Ten Years of Routine alpha- and beta-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations. Hemoglobin. 2016;40(2):75-84. Lacan P et al. Hb aubagne [beta64(E8)Gly-Ala]: a new unstable beta chain variant found in a French family. Hemoglobin. 2002 May;26(2):163-7. Marinucci M et al. Studies on a family with Hb J Calabria (alpha 2 beta 2 64 (E8) Gly replaced by Asp). Hemoglobin. 1979;3(5):327-40. -

HEMOGLOBIN AUBAGNE 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	0.95
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.6	H;H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.7	D;.;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.018	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.66
MutPred		0.93		Loss of disorder (P = 0.1);Loss of disorder (P = 0.1);Loss of disorder (P = 0.1);Loss of disorder (P = 0.1);
MVP		0.97
MPC		0.23
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.86

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: rs33922018; hg19: chr11-5247928;