rs34387455

Variant names:

• chr11-5226999-T-C
• rs34387455
• NM_000518.5:c.23A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000518.5(HBB):​c.23A>G​(p.Glu8Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E8K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 7.13

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5227000-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.23A>G	p.Glu8Gly	missense_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.23A>G	p.Glu8Gly	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251184 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459982 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 28, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.23A>G (p.Glu8Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251184 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.23A>G has been reported in the literature in a healthy individual in homozygosity (Brancati_1989) as well as in several healthy carriers (e.g. Smith_2016, Zhang_2022). The variant is known in the literature as a rare polymorphism that has been reported mostly in Southern Italian or of Mexican families (Lacerra_2002). Individuals who have the variant of interest together with b-thal mutation are likely to have hematological values reflecting their b-thal carrier status. Studies of functional properties confirmed that the variant protein has normal oxygen affinity, cooperativity and Bohr effect with a slightly decreased stability that may have only a marginal role, considering that the variant is not associated with a clinically significant hemolytic process (Roth_1977, Lacerra_2002). The following publications have been ascertained in the context of this evaluation (PMID: 11939513, 2599885, 26524961, 949549, 36226750). ClinVar contains an entry for this variant (Variation ID: 15176). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Nov 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb G-San Jose variant (HBB c.23A>G; p.Glu8Gly, also known as Glu7Gly when numbered from the mature protein, rs34387455, HbVar ID: 230, ClinVar Variation ID: 15176), is not associated with any clinically significant symptoms in individuals who are homozygous carriers of the variant, or compound heterozygous with a pathogenic HBB variant (Lacerra 2002, Musumeci 1979, see HbVar link). This variant has been reported to have normal Bohr effect, cooperativity, and oxygen affinity, but is slightly unstable at elevated temperatures (Roth 1977). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.83). However, due to the absence of associated clinical symptoms, the Hb G-San Jose variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Lacerra G et al. Hb G-San Jose variant levels correlate with alpha-thalassemia genotypes. Hemoglobin. 2002 Feb;26(1):59-66. PMID: 11939513. Musumeci S et al. Hemoglobin G San Jose (beta 2 7 (A4) Glu to Gly alpha 2), beta thalassemia, and alpha thalassemia in a Sicilian family. Hum Genet. 1979 Nov;52(2):239-47. PMID: 511180. Roth EF Jr et al. Some properties of Hb G San Jose (beta7 glu replaced by gly): comparisons with Hb S. J Lab Clin Med. 1977 Nov;90(5):837-43. PMID: 20481. -

HEMOGLOBIN G (SAN JOSE) Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.7	D;.;.;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		0.97	D;D;.;.
Vest4		0.93
MutPred		0.79		Loss of stability (P = 0.0461);Loss of stability (P = 0.0461);Loss of stability (P = 0.0461);Loss of stability (P = 0.0461);
MVP		0.99
MPC		0.27
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.84

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: rs34387455; hg19: chr11-5248229;