11-5225668-G-C

Variant names:

• chr11-5225668-G-C
• rs33983276
• NM_000518.5:c.374C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000518.5(HBB):​c.374C>G​(p.Pro125Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,132 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P125S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 5.97

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 11-5225668-G-C is Pathogenic according to our data. Variant chr11-5225668-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15238.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.374C>G	p.Pro125Arg	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.374C>G	p.Pro125Arg	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2023	The Hb Khartoum variant (HBB: c.374C>G p.Pro125Arg, also known as Pro124Arg when numbered from the mature protein, rs33983276, HbVar ID: 515) is reported in the heterozygous state in individuals with normal clinical presentation (Bayoumi 1999, Hendy 1999, see HbVar and references therein). However, its phenotype when found with a pathogenic HBB variant on the opposite chromosome is unknown.This variant is also reported in ClinVar (Variation ID: 15238), is but absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.747). Due to limited information, the clinical significance of the Hb Khartoum variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Bayoumi RA et al. The association of Hb Khartoum (beta124(H2)Pro-->Arg) with gamma+-thalassemia is responsible for hemolytic disease in the newborn of a Sudanese family. Hemoglobin. 1999 Feb;23(1):33-45. PMID: 10081984. Hendy JG et al. Hb Khartoum (beta124(H2)Pro-->Arg) in a Vietnamese female. Hemoglobin. 1999 Aug;23(3):291-3. PMID: 10490144. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 19, 2024	The HBB c.374C>G (p.Pro125Arg) variant (also known as Hb Khartoum or P124R) has been reported in the published literature to be mildly unstable, though without clinical or laboratory evidence of disease in heterozygous carriers (PMIDs: 5782115 (1969), 10490144 (1999), 26635043 (2016)). It was reported in one family where two heterozygous children were born with severe jaundice and required blood transfusions. In this family, gamma globin variants were considered to be involved and no further complications were observed (PMID: 10081984 (1999)). The frequency of this variant in the general population, 0.000015 (1/68028 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant. -

Hemoglobinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 20, 2018

Variant summary: HBB c.374C>G (p.Pro125Arg) results in a non-conservative amino acid change in the encoded protein sequence. The variant is also reported in the literature as Hb Khartoum. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246070 control chromosomes (gnomAD). c.374C>G has been reported in the literature in a Sudanese family, together with potentially pathogenic variants in the A-gamma (HBG1) and G-gamma (HBG2) genes, in 2 newborns who were affected with severe neonatal jaundice at birth and chronic mild hemolytic anemia during the first year of life, and the variant showed complete segregation with the disease (Bayoumi 1999). Heterozygous carriers in this family had no major hematological phenotypes (Bayoumi 1999), in addition the variant was also reported in a Vietnamese heterozygous carrier, in whom all hematological values were within the normal range (Hendy 1999); these reports suggest that Hb Khartoum alone does not seem to cause any clinical or hematological abnormalities. At least one publication reported experimental evidence and demonstrated only minor changes in protein stability, concluding that the variant protein is probably not unstable in vivo, however no further functional studies (e.g. for oxygen binding properties) were performed (Clegg 1969). Other variants at the same nucleotide position have been reported as associated with disease (c.374C>A, c.374C>T in HGMD), as well as in adjacent codons (e.g. p.T124I and p.V127E), all of which support a pathogenic role for the variant. Several reputable databases have classified the variant as a causative variant (e.g. HbVar and Ithanet). Overall, these data indicate that the variant is likely to be associated with disease. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

HEMOGLOBIN KHARTOUM 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.86	.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.5	H;H
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.76		Gain of MoRF binding (P = 0.0509);Gain of MoRF binding (P = 0.0509);
MVP		0.99
MPC		0.25
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.28
gMVP		0.91

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: rs33983276; hg19: chr11-5246898;