11-5226952-C-G

Position:

• chr11-5226952-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000518.5(HBB):​c.70G>C​(p.Val24Leu) 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 benign outcome for this variant. 12/21 in silico tools predict a benign 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. V24A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0490

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 5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 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 chr11-5226952-C-A is described in ClinVar as [Pathogenic, other]. Clinvar id is 15306.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3742712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.70G>C	p.Val24Leu	missense_variant	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.70G>C	p.Val24Leu	missense_variant	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 27, 2017

Variant summary: The HBB c.70G>C (p.Val24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant is absent from control datasets of ExAC and gnomAD (121364 and 246060 chrs tested, respectively). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or cited by clinical diagnostic laboratories, nor was it evaluated for functional impact by in vivo/vitro studies. The Val24 codon appears to be a mutation hot-spot, as other alterations, such as p.Val24Ala, p.Val24Asp, p.Val24Ile, p.Val24Phe and p.Val24Gly, have been reported in publications as causative in association with hemoglobinopathies. Due to the lack of clinical information and absence of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.034	T;T;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.4	N;.;.;N
REVEL	Uncertain	0.61
Sift	Benign	0.098	T;.;.;T
Sift4G	Benign	0.25	T;.;.;.
Polyphen		0.0030	B;B;.;.
Vest4		0.43
MutPred		0.48		Loss of catalytic residue at G25 (P = 0.2143);Loss of catalytic residue at G25 (P = 0.2143);Loss of catalytic residue at G25 (P = 0.2143);Loss of catalytic residue at G25 (P = 0.2143);
MVP		0.58
MPC		0.034
ClinPred		0.057	T
GERP RS		-1.3
Varity_R		0.41
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs33929459; hg19: chr11-5248182;