rs63750717

Positions:

• chr11-5226991-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4 BP6

The ENST00000335295.4(HBB):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. A11D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HBB ENST00000335295.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.993

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 15 uncertain in ENST00000335295.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34648377).
• BP6: Variant 11-5226991-C-T is Benign according to our data. Variant chr11-5226991-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439152.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.31G>A	p.Ala11Thr	missense_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.31G>A	p.Ala11Thr	missense_variant	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460958 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726878

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2022	Variant summary: HBB c.31G>A (p.Ala11Thr) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251216 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.31G>A (also known as Hb Belleville) has been reported in the literature in heterozygous individuals and was described as causing no apparent clinical manifestations (e.g. Williams_2009). These report(s) 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. A ClinVar submitter (evaluation after 2014) cites the variant as likely benign without providing evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 12, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.59
DANN	Benign	0.87
DEOGEN2	Benign	0.033	T;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	.;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.1	L;L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;.;.;N
REVEL	Uncertain	0.53
Sift	Benign	0.14	T;.;.;D
Sift4G	Benign	0.57	T;.;.;.
Polyphen		0.0010	B;B;.;.
Vest4		0.46
MutPred		0.26		Gain of glycosylation at S10 (P = 0.0991);Gain of glycosylation at S10 (P = 0.0991);Gain of glycosylation at S10 (P = 0.0991);Gain of glycosylation at S10 (P = 0.0991);
MVP		0.61
MPC		0.036
ClinPred		0.15	T
GERP RS		-2.0
Varity_R		0.087
gMVP		0.67

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: rs63750717; hg19: chr11-5248221;