11-5226693-T-C

Position:

• chr11-5226693-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000518.5(HBB):​c.199A>G​(p.Lys67Glu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K67T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.53

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 11 ACMG points.

• PM1: In a hotspot region, there are 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226692-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15136.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-5226693-T-C is Pathogenic according to our data. Variant chr11-5226693-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15206.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr11-5226693-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.199A>G	p.Lys67Glu	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.199A>G	p.Lys67Glu	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hemoglobinopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 27, 1971

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 18, 2022

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, individuals heterozygous for this variant present with chronic mild hemolytic anemia (PMID: 35898763 (2022), 7928379 (1994), 3583764 (1987), 5791730 (1969)). In a functional study, this variant exhibited minor alterations in function in an assay that evaluated oxidation and reduction rates (PMID: 7407240 (1980)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 16, 2024

Variant summary: HBB c.199A>G (p.Lys67Glu) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251432 control chromosomes. c.199A>G has been reported in the literature as a heterozygous genotype in settings of mild chronic hemolytic anemia with unstable hemoglobin and increased methemoglobin levels (cited in Xu_2022, Rosa_1969), and low oxygen saturations (Xu_2022). It has also been reported as a compound heterozygous genotype with HbS in at-least one individual with joint pain and hemolytic anemia (Tejuca_1987) and in settings of a co-existing diagnosis of alpha thallasemia (example, Hendy_1994, Pullon_2016). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7928379, 5791730, 3583764, NO_PMID for Pullon_2016). ClinVar contains an entry for this variant (Variation ID: 15206). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.7	D;.;.;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.0060	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.85
MutPred		0.97		Gain of ubiquitination at K66 (P = 0.027);Gain of ubiquitination at K66 (P = 0.027);Gain of ubiquitination at K66 (P = 0.027);Gain of ubiquitination at K66 (P = 0.027);
MVP		0.99
MPC		0.16
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.79

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: rs34165323; hg19: chr11-5247923;