11-5226617-A-C

Position:

• chr11-5226617-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000518.5(HBB):​c.275T>G​(p.Leu92Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L92P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.58

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.275T>G	p.Leu92Arg	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.275T>G	p.Leu92Arg	missense_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2021	The Hb Caribbean variant (HBB: c.275T>G; p.Leu92Arg, also known as Leu91Arg when numbered from the mature protein, rs33917785), is reported in the literature in the heterozygous state or in combination with Hb S in individuals with mild anemia or normal hematology (see link to HbVar and references therein, Ahern 1976). In vitro functional analyses demonstrate a mildly unstable protein with decreased oxygen affinity (Ahern 1976). This variant is also reported in ClinVar (Variation ID: 15131), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 92 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.885). However, given the limited amount of clinical and functional data, the significance of the Hb Caribbean variant is uncertain at this time. References: Link to HbVar for Hb Caribbean: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=428 Ahern E et al. Haemoglobin caribbean beta91 (F7) Leu replaced by Arg: a mildly haemoglobin with a low oxygen affinity. FEBS Lett. 1976 Oct 15;69(1):99-102. PMID: 992050. -

HEMOGLOBIN CARIBBEAN 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	0.54
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.0	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.4	D;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.030	D;.;.
Polyphen		0.97	D;D;.
Vest4		0.96
MutPred		0.87		Loss of stability (P = 0.0071);Loss of stability (P = 0.0071);Loss of stability (P = 0.0071);
MVP		0.93
MPC		0.28
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.96

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: rs33917785; hg19: chr11-5247847;