rs35485099

Variant names:

• chr11-5225695-G-A
• rs35485099
• NM_000518.5:c.347C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5225695-G-A
• chr11-5225695-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000518.5(HBB):​c.347C>T​(p.Ala116Val) variant causes a missense change. 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. A116D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 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 chr11-5225695-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 15526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.347C>T	p.Ala116Val	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.347C>T	p.Ala116Val	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2025

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.347C>T (p.Ala116Val) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251276 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.347C>T has been observed in the heterozygous state in an individual affected with mild hypochromia and microcytosis (Manconi_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Beta Thalassemia. At least one publication reports experimental evidence that this variant results in increased oxygen affinity (Manconi_2010). Different variants affecting the same codon have been classified as pathogenic by our lab in association with autosomal dominant Beta thalassemia (c.347C>A(p.Ala116Asp) & c.346G>C (p.ALa116Pro)), supporting the critical relevance of codon 116 to HBB protein function. This variant is also known as Hb Roma. The following publication have been ascertained in the context of this evaluation (PMID: 19900509). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	4.5	H;H
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		0.64	P;P
Vest4		0.66
MutPred		0.66		Loss of ubiquitination at K121 (P = 0.1264);Loss of ubiquitination at K121 (P = 0.1264);
MVP		0.83
MPC		0.094
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.45
gMVP		0.86
Mutation Taster		=5/95	disease causing

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: rs35485099; hg19: chr11-5246925;