11-5225668-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P125S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 15 uncertain in NM_000518.5
• 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 [Likely_pathogenic]. Clinvar id is 15238.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.374C>G	p.Pro125Arg	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.374C>G	p.Pro125Arg	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.374C>G	p.Pro125Arg	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.306C>G		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*190C>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	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: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D
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;