11-5225668-G-A

Position:

• chr11-5225668-G-A

Variant summary

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

The NM_000518.5(HBB):​c.374C>T​(p.Pro125Leu) 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. P125S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 5.97

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 15 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225668-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15238.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.374C>T	p.Pro125Leu	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.374C>T	p.Pro125Leu	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.374C>T	p.Pro125Leu	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.306C>T		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*190C>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2020	Variant summary: HBB c.374C>T (p.Pro125Leu) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. This variant is also known in the literature as "Hemoglobin Tende" or as the legacy name p.Pro124Leu. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.374C>T has been reported in the literature in at least two asymptomatic carriers with hemoglobin variants (examples- Wajcman_1998, Sangkitporn_2008). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in a 30-50% increase in oxygen affinity (Wajcman_1998). Two of three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (one submitter did not provide a clinical classification). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2019	The Hb Tende variant (HBB: c.374C>T; p.Pro125Leu, also known as Pro124Leu when numbered from the mature protein, rs33983276) is described as having a normal clinical presentation in heterozygous carriers (see HbVar database, Sangkitporn 2009); however, its phenotype when found with a pathogenic HBB variant on the opposite chromosome is unknown. Functional studies show a moderate increase in oxygen affinity (see HbVar database). A different variant at this codon (Hb Ty Gard: c.374C>A; p.Pro125Gln) is reported with high oxygen affinity and is associated with erythrocytosis (see HbVar database). The Hb Tende variant contains an entry in the ClinVar database (Variation ID: 15569). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 125 is highly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the Hb Tende variant is uncertain at this time. REFERENCES HbVar link for Hb Tende: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=518&.cgifields=histD HbVar link for Hb Ty Gard: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=516&.cgifields=histD Sangkitporn SK et al. Identification of beta-globin gene mutations in Thailand using an automated fluorescence-based DNA sequencer. Int J Lab Hematol. 2009 Oct;31(5):521-7. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 07, 2017

- -

HEMOGLOBIN TENDE 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.6	D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.061	T;.
Polyphen		0.97	D;D
Vest4		0.84
MutPred		0.72		Loss of disorder (P = 0.0293);Loss of disorder (P = 0.0293);
MVP		0.95
MPC		0.065
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.19
gMVP		0.91

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: rs33983276; hg19: chr11-5246898;