rs34868397

Positions:

• chr11-5226758-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000518.5(HBB):​c.134C>G​(p.Ser45Cys) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:1
• Conservation: PhyloP100: -3.45

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.134C>G	p.Ser45Cys	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.134C>G	p.Ser45Cys	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1978

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 09, 2021

The Hb Mississippi variant (HBB: c.134C>G; p.Ser45Cys, also known as Ser44Cys when numbered from the mature protein, rs34868397) is reported to be a mildly unstable hemoglobin variant. Hb Mississippi heterozygotes are clinically and hematologically normal, however, Hb Mississippi in trans to a Beta(+)-thalassemia allele is reported to cause a thalassemia intermedia phenotype (Steinberg 1987). The Hb Mississippi variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 45 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.711). However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar link to Hb Mississippi: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=319&.cgifields=histD Steinberg MH et al. Hemoglobin Mississippi (beta 44ser----cys). Studies of the thalassemic phenotype in a mixed heterozygote with beta +-thalassemia. J Clin Invest. 1987 Mar;79(3):826-32. PMID: 2434529. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	T;T;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.088	N
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.7	H;H;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.7	D;.;.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.015	D;.;.;.
Polyphen		0.95	P;P;.;.
Vest4		0.86
MutPred		0.69		Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);
MVP		0.93
MPC		0.16
ClinPred		0.99	D
GERP RS		-2.4
Varity_R		0.75
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: rs34868397; hg19: chr11-5247988;