chr11-5226680-G-C

Position:

• chr11-5226680-G-C

Variant summary

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

The ENST00000335295.4(HBB):​c.212C>G​(p.Ala71Gly) 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. A71D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB ENST00000335295.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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 4 benign, 14 uncertain in ENST00000335295.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226681-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.212C>G	p.Ala71Gly	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.212C>G	p.Ala71Gly	missense_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jun 27, 2023

The HBB c.212C>G (p.Ala71Gly, also known as Hb Hershey) variant has been reported to have decreased oxygen affinity and associated with hemolytic anemia. In the published literature, this variant was identified in an individual with hemolytic anemia and microcytosis. This individual was found to also carry the HBB IVS1-1G>A pathogenic variant (PMID: 16370483 (2005)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T;T;.;T
Eigen	Benign	0.071
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.91	L;L;.;.
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N;.;.;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D;.;.;D
Sift4G	Benign	0.80	T;.;.;.
Polyphen		0.25	B;B;.;.
Vest4		0.88
MutPred		0.77		Loss of stability (P = 0.0688);Loss of stability (P = 0.0688);Loss of stability (P = 0.0688);Loss of stability (P = 0.0688);
MVP		0.79
MPC		0.036
ClinPred		0.64	D
GERP RS		5.1
Varity_R		0.58
gMVP		0.79

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: rs33946401; hg19: chr11-5247910;