NM_000518.5:c.380T>A

Variant names:

• chr11-5225662-A-T
• rs33925391
• NM_000518.5:c.380T>A
• HBB p.Val127Glu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingO7_Moderate

The NM_000518.5(HBB):c.380T>A (p.Val127Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene HBB is a known oncogene (CancerMine: 4 oncogene, 1 driver citations). The gene HBB is a cancer driver gene (CancerMine: 4 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,774 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000224. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V127A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15106); p.V127G: Uncertain_significance (ClinVar VariationId 15483, 3 stars); p.V127L: other (ClinVar VariationId 15597, 0 stars); p.V127= (synonymous): Likely_benign (ClinVar VariationId 1142046, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3 O:1
• Conservation: PhyloP100: 0.0220
• Publications: 19 publications found

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]

HBB Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, Natera
• erythrocytosis, familial, 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, Ambry Genetics
• unstable hemoglobin disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women's Health
• beta-thalassemia and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• sickle cell disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, Natera
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary persistence of fetal hemoglobin

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• delta-beta-thalassemia

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000022, AC = 2 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Moderate: ≥10 same AA change, or strong functional domain signal; No cancerhotspots.org hit at this position; UniProt domain: 131 pathogenic, 51 benign (OR vs. background: 12.8).; ±8 AA neighbourhood: 11 pathogenic, 5 benign (OR vs. background: 10.5); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000518.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HBB NM_000518.5	MANE Select	c.380T>A p.Val127Glu	missense	Exon 3 of 3	Prot: NP_000509.1 UniProt:

HBB NM_000518.5

MANE Select

HGVSc / HGVSpc.380T>Ap.Val127Glu

Exon rankExon 3 of 3

missense

Prot: NP_000509.1UniProt: P68871D9YZU5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HBB ENST00000335295.4	TSL:1MANE Select	c.380T>A p.Val127Glu	missense	Exon 3 of 3	Prot: ENSP00000333994.3 UniProt:
	HBB ENST00000647020.1		c.380T>A p.Val127Glu	missense	Exon 3 of 3	Prot: ENSP00000494175.1 UniProt:
	HBB ENST00000883533.1		c.380T>A p.Val127Glu	missense	Exon 4 of 4	Prot: ENSP00000553592.1 UniProt:

HBB ENST00000335295.4

TSL:1MANE Select

HGVSc / HGVSpc.380T>Ap.Val127Glu

Exon rankExon 3 of 3

missense

Prot: ENSP00000333994.3UniProt: P68871

HBB ENST00000647020.1

HGVSc / HGVSpc.380T>Ap.Val127Glu

Exon rankExon 3 of 3

missense

Prot: ENSP00000494175.1UniProt: P68871

HBB ENST00000883533.1

HGVSc / HGVSpc.380T>Ap.Val127Glu

Exon rankExon 4 of 4

missense

Prot: ENSP00000553592.1UniProt: P68871

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461774	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	beta Thalassemia (3)
-	2	-	not provided (2)
1	-	-	Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB (1)
-	1	-	not specified (1)
-	-	-	HEMOGLOBIN HOFU (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.30	N
FuncVEP CTI	Pathogenic	0.71
GPN-Star LLR	N/A	-5.3
GPN-Star score	N/A	5.3
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.26	D
Mutation Taster	N/A	3/97	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.5	H
PhyloP100	Benign	0.022
popEVE	Benign	-3.9
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Varity_R	N/A	0.51
VESM-3B	Benign	-10

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs33925391;

hg19: chr11-5246892;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar