11-5227014-T-G

Position:

• chr11-5227014-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000518.5(HBB):​c.8A>C​(p.His3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.62

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 9 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 chr11-5227013-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.8A>C	p.His3Pro	missense_variant	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.8A>C	p.His3Pro	missense_variant	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2019	Variant summary: HBB c.8A>C (p.His3Pro), also known as Hb Long Island-Marseille and Hb Agrigente in the literature and variant databases, 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 251140 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8A>C has been reported in the literature as an abnormal hemoglobin detected during HbA1C evaluation in diabetic patients who were otherwise hematologically normal (Barwick_1985, Blouquit_1984, Boi_1989, Wei_2019). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance until additional clinical and functional evidence becomes available. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1989	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T;T;.;T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.5	D;.;.;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.016	D;.;.;.
Polyphen		0.49	P;P;.;.
Vest4		0.59
MutPred		0.54		Gain of glycosylation at H3 (P = 0.0374);Gain of glycosylation at H3 (P = 0.0374);Gain of glycosylation at H3 (P = 0.0374);Gain of glycosylation at H3 (P = 0.0374);
MVP		0.88
MPC		0.097
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.68
gMVP		0.69

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: rs33983205; hg19: chr11-5248244;