11-5225708-C-G

Variant names:

• chr11-5225708-C-G
• rs33957964
• NM_000518.5:c.334G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4 BP6

The NM_000518.5(HBB):​c.334G>C​(p.Val112Leu) 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. 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. V112A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.377

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]

ENSG00000285498 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225707-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2838235).
• BP6: Variant 11-5225708-C-G is Benign according to our data. Variant chr11-5225708-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478878.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.334G>C	p.Val112Leu	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.334G>C	p.Val112Leu	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Sep 18, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.334G>C (p.Val112Leu) results in a conservative amino acid change located in the Globin domain (Globin) 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 251234 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.334G>C has been reported in the literature cis with another missense variant in individuals without clinical features of Beta Thalassemia (Qin_1994). These report(s) do not provide unequivocal conclusions about association of the variant with Beta Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 7852084). ClinVar contains an entry for this variant (Variation ID: 478878). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Nov 23, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.53
Sift	Benign	0.040	D;.
Sift4G	Benign	0.67	T;.
Polyphen		0.013	B;B
Vest4		0.40
MutPred		0.57		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP		0.55
MPC		0.035
ClinPred		0.37	T
GERP RS		4.7
Varity_R		0.51
gMVP		0.81

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: rs33957964; hg19: chr11-5246938;