11-5226978-A-C

Variant names:

• chr11-5226978-A-C
• rs33935445
• NM_000518.5:c.44T>G

Variant summary

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

The NM_000518.5(HBB):​c.44T>G​(p.Leu15Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,162 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 3.64

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, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.44T>G	p.Leu15Arg	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.44T>G	p.Leu15Arg	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461162 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726914

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Nov 06, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Sogn variant (HBB: c.44T>G; p.Leu15Arg, also known as p.L14R when numbered from the mature protein, rs33935445, HbVar ID: 243, ClinVar ID: 15355) is reported in the literature in multiple clinically healthy heterozygous individuals (Fairbanks 1990). This variant has also been reported in heterozygosity in combination with alpha-thal-2 trait in an individual with microcytosis and hypochromia (Miller 1996). This variant does not separate from Hb S during electrophoresis (see link to HbVar and references therein). This variant is reported as mildly unstable (HbVar). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.797). Due to limited information, the clinical significance of the p.Leu15Arg variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Miller DR et al. Hb Sogn or alpha 2 beta 2 14(A11)Leu-->Arg in combination with an alpha-thalassemia heterozygosity. Hemoglobin. 1996 May;20(2):131-4. PMID: 8811316 Fairbanks VF et al. Two families with hemoglobin Sogn, beta(A11)14 Leu----Arg, in Minnesota and Indiana: hematologic, functional, and biosynthetic features. Mayo Clin Proc. 1990 Jun;65(6):793-8. PMID: 2366586. -

not specified Uncertain:1

Dec 03, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.44T>G (p.Leu15Arg) results in a non-conservative amino acid change in 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 251236 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.44T>G has been reported in the literature in asymptomatic carriers who were hematologically normal, as well as a heterozygous proband with microcytosis and hypochromia who was also heterozygous with an alpha-thalassemia-2 allele (e.g. Monn_1970, Fairbanks_1990, Miller_1996). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Experimental evidence found that the variant results in a less stable protein than the wild type (Mann_1970, Fairbanks_1990), however, does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 8811316, 2366586, 4994348). ClinVar contains an entry for this variant (Variation ID: 15355). Based on the evidence outlined above, the variant was classified as uncertain significance. -

beta Thalassemia Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

HEMOGLOBIN SOGN Other:1

Dec 12, 2017

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	0.71
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;T;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.0	H;H;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.5	D;.;.;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.0070	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.77
MutPred		0.77		Loss of stability (P = 0.0469);Loss of stability (P = 0.0469);Loss of stability (P = 0.0469);Loss of stability (P = 0.0469);
MVP		0.88
MPC		0.29
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs33935445; hg19: chr11-5248208;