11-5226936-A-G

Variant names:

• chr11-5226936-A-G
• rs33916412
• NM_000518.5:c.86T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):​c.86T>C​(p.Leu29Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L29M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 8.44

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226937-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-5226936-A-G is Pathogenic according to our data. Variant chr11-5226936-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15183.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.86T>C	p.Leu29Pro	missense_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.86T>C	p.Leu29Pro	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hemoglobinopathy Pathogenic:1

Sep 17, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.86T>C (p.Leu29Pro), known as Hemoglobin Genova, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes. c.86T>C has been reported in the literature as an unstable hemoglobin characterized by Heinz bodies and hemolytic anemia in multiple affected individuals from diverse global ethnic backgrounds (example, Sansone_1967, Solal_1973, Martinez_1983, Hopmeier_1990, Kitazawa_2000, Badens_2005). Although most of the ascertained reports did not clearly indicate the exact zygosity of the variant identified in each proband, at-least one report of this variant in compound heterozygosity with a beta-0-thal variant in a case of early onset thalassemia major syndrome (beta-thal major phenotype) has been reported (Badens_2005). It continues to be subsequently cited by others in the field (example Wajcman_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased oxygen affinity and an underlying instability (example Solal_1973). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, although the OMIM database has submitted this variant without an interpretation and/or an assertion criteria. Based on the evidence outlined above, the variant was classified as pathogenic. -

HEMOGLOBIN GENOVA Other:1

Jan 01, 1990

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN HYOGO Other:1

Jan 01, 1990

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;T;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.9	D;.;.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.95
MutPred		0.91		Loss of stability (P = 0.023);Loss of stability (P = 0.023);Loss of stability (P = 0.023);Loss of stability (P = 0.023);
MVP		0.93
MPC		0.30
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33916412; hg19: chr11-5248166;