11-5226735-C-G

Position:

• chr11-5226735-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The ENST00000335295.4(HBB):​c.157G>C​(p.Asp53His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D53A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB ENST00000335295.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: -1.65

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 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 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 chr11-5226735-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.157G>C	p.Asp53His	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.157G>C	p.Asp53His	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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 11, 2018

The Hb Summer Hill variant (c.157G>C, Asp52His) has been observed in a sample submitted for thalassemia/hemoglobinopathy screening (Turner 2016), but it is reported to be functionally equivalent to Hb A and is not associated with significant clinical symptoms (HbVar database and references therein). However, its phenotype when found with other globin variants is unknown. It is listed in the dbSNP variant database (rs33961886), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The aspartate at residue 52 is weakly conserved, but computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) are inconclusive on the variant's impact on the protein. Due to the limited information regarding this variant, its clinical significance is uncertain. References: Link to HbVar database for Hb Summer Hill: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=336 Turner A et al. Rapid detection of pathological mutations and deletions of the haemoglobin beta gene (HBB) by High Resolution Melting (HRM) analysis and Gene Ratio Analysis Copy Enumeration PCR (GRACE-PCR). BMC Med Genet. 2016 Oct 19;17(1):75. -

beta Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 09, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 06, 2020

The HBB c.157G>C (p.Asp53His) variant, also known as Hb Summer Hill, has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant was found in a Lebanese woman (PMID: 7190137 (1980)) and in a Turkish family from Cyprus with no hematological abnormalities (PMID: 6629828 (1983)). This variant has been described as rare beta-chain variant (PMID: 26635043 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

HEMOGLOBIN SUMMER HILL 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	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	6.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	.;T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N;.;.;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.012	D;.;.;D
Sift4G	Benign	0.10	T;.;.;.
Polyphen		0.20	B;B;.;.
Vest4		0.49
MutPred		0.49		Loss of phosphorylation at T51 (P = 0.114);Loss of phosphorylation at T51 (P = 0.114);Loss of phosphorylation at T51 (P = 0.114);Loss of phosphorylation at T51 (P = 0.114);
MVP		0.95
MPC		0.17
ClinPred		0.61	D
GERP RS		-4.8
Varity_R		0.24
gMVP		0.53

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: rs33961886; hg19: chr11-5247965;