11-5226629-G-T

Position:

• chr11-5226629-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000518.5(HBB):​c.263C>A​(p.Thr88Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T88I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 0.799

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 8 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.120817035).
• BP6: Variant 11-5226629-G-T is Benign according to our data. Variant chr11-5226629-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15150.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.263C>A	p.Thr88Lys	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.263C>A	p.Thr88Lys	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2024	Variant summary: HBB c.263C>A (p.Thr88Lys), also known as Hb D-Ibadan, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.263C>A has been reported in a propositus and his mother in a Nigerian family who were compound heterozygous for this variant and pathogenic HbS allele and both were clinically asymptomatic (Watson-Williams_1965). Similarly, in two other subjects of African-American ethnicity, compound heterozygosity with other pathogenic variant (HbS and c.-79A>G) failed to cause disease (Redding-Lallinger_2002). Additionally, one reported case who was compound heterozygosity with HbC only showed mild anemia phenotype (Kundrapu_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 6859036, 974261, 284392, 14311973, 12144055, 27207683, 30604644). ClinVar contains an entry for this variant (Variation ID: 15150). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 20, 2017	- -

beta Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 18, 2020

- -

HEMOGLOBIN D (IBADAN) 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	0.055
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	0.18
DANN	Benign	0.64
DEOGEN2	Benign	0.018	T;T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.040	.;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-1.9	N;N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.3	N;.;.;N
REVEL	Uncertain	0.54
Sift	Benign	1.0	T;.;.;T
Sift4G	Benign	1.0	T;.;.;.
Polyphen		0.0	B;B;.;.
Vest4		0.87
MutPred		0.36		Gain of ubiquitination at T88 (P = 0.0211);Gain of ubiquitination at T88 (P = 0.0211);Gain of ubiquitination at T88 (P = 0.0211);Gain of ubiquitination at T88 (P = 0.0211);
MVP		0.45
MPC		0.038
ClinPred		0.062	T
GERP RS		-7.3
Varity_R		0.18
gMVP		0.66

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: rs33993568; hg19: chr11-5247859;