chr11-5227002-T-G

Position:

• chr11-5227002-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000518.5(HBB):​c.20A>C​(p.Glu7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.690

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5227003-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.37789398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.20A>C	p.Glu7Ala	missense_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.20A>C	p.Glu7Ala	missense_variant	1/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458400 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2023

Variant summary: HBB c.20A>C (p.Glu7Ala), also known as the Hb G Makassar variant, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251180 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, c.20A>C has been reported in the literature in several healthy homozygous and heterozygous individuals, who were exclusively of Thai and Indonesian descent and identified as having abnormal hemoglobin bands through HPLC analysis, but were found to have normal blood test results and no clinical abnormalities (e.g., Blackwell_1970, Viprakasit_2002, Thongnoppakhun_2009, Saechan_2010, Sangkitporn_2002). In a compound heterozygous individual where a pathogenic variant was identified in trans, the individual only displayed a Beta-thalassemia minor phenotype (e.g., Viprakasit_2002). At least one publication reports experimental evidence evaluating an impact on protein function, showing that c.20A>C represents a benign variant that rescued the disease phenotype in a humanized mouse sickle cell model (e.g., Newby_2021). The following publications have been ascertained in the context of this evaluation (PMID: 1363932, 5509617, 34079130, 20838957, 12188388, 19460936, 12403489). One ClinVar submitter (evaluation after 2014) has cited the variant as other (in reference to Blackwell_1970 in which the variant was identified in a healthy heterozygous individual). Based on the evidence outlined above, the variant was classified as likely benign. -

HEMOGLOBIN G (MAKASSAR) 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	Benign	0.083
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	7.9
DANN	Benign	0.80
DEOGEN2	Benign	0.080	T;T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.3	L;L;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	D;.;.;D
REVEL	Uncertain	0.50
Sift	Benign	0.35	T;.;.;T
Sift4G	Benign	0.58	T;.;.;.
Polyphen		0.0	B;B;.;.
Vest4		0.79
MutPred		0.42		Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);
MVP		0.94
MPC		0.035
ClinPred		0.077	T
GERP RS		0.15
Varity_R		0.26
gMVP		0.55

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: rs334; hg19: chr11-5248232;