chr11-5226718-G-T

Position:

• chr11-5226718-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000518.5(HBB):​c.174C>A​(p.Asn58Lys) 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 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. N58D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: -0.246

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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.174C>A	p.Asn58Lys	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.174C>A	p.Asn58Lys	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 01, 2021

The Hb G-Ferrara variant (HBB c.174C>A; p.Asn58Lys, also known as Asn57Lys when numbered from the mature protein, rs35278874) is reported as a slightly unstable hemoglobin, but shows normal oxygen affinity, Bohr effect and cooperativity (HbVar database and references therein). In one study, the data suggested that Hb G-Ferrara in combination with Hb S could result in sickle cell disease (see Canizares 1983, discussed in Silva 2013); however, a later study suggests Hb G-Ferrara is not associated with sickle cell disease (Silva 2013). The Hb G-Ferrara variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 58 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.639). Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Link to HbVar database for Hb G-Ferrara: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=344 Canizares ME et al. Hemoglobinopatia S con interaccion de la HbS y la Hb G-Ferrara [Hemoglobinopathy S with an interaction of HbS and Hb G-Ferrara]. Sangre (Barc). 1983;28(6):770-4. Spanish. PMID: 6673168. Silva MR et al. Clinical and molecular characterization of hemoglobin Maputo [beta 47 (CD6) Asp > Tyr HBB: c.142G > T] and G-Ferrara [beta 57 (E1) Asn > Lys HBB: c.174C > A] in a newborn screening in Brazil. Int J Lab Hematol. 2013 Dec;35(6):e1-4. PMID: 23279838. -

HEMOGLOBIN G (FERRARA) 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	9.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;.;.
MutationTaster	Benign	0.69	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.5	D;.;.;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.94
MutPred		0.88		Gain of methylation at N58 (P = 0.0311);Gain of methylation at N58 (P = 0.0311);Gain of methylation at N58 (P = 0.0311);Gain of methylation at N58 (P = 0.0311);
MVP		0.91
MPC		0.27
ClinPred		0.99	D
GERP RS		-7.7
Varity_R		0.89
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: rs35278874; hg19: chr11-5247948; COSMIC: COSV58942200; COSMIC: COSV58942200;