11-5225662-A-C

Variant names:

• chr11-5225662-A-C
• rs33925391
• NM_000518.5:c.380T>G
• HBB p.Val127Gly

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3

The NM_000518.5(HBB):c.380T>G (p.Val127Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000205 (AC=3) in the gnomAD database across 1,461,774 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. 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 Uncertain Significance (★★★). ClinVar reports functional evidence for this variant: "SCV001361819: The variant protein was demonstrated to be unstable under certain in vitro conditions (Pagano_1991, Divoky_1992).". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.V127E: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15201) 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.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: 0.0000021 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 0.0220
• Publications: 1 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001361819: The variant protein was demonstrated to be unstable under certain in vitro conditions (Pagano_1991, Divoky_1992).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 131 pathogenic, 51 benign rare missense variants (OR vs. background: 12.8).; ±8 AA neighbourhood: 11 pathogenic, 5 benign (OR vs. background: 10.5).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000116 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00265) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.V127E: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15201); Other variants at the same amino acid residue (not pathogenic): p.V127A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15106); p.V127L: other (ClinVar VariationId 15597, 0 stars); p.V127= (synonymous): Likely_benign (ClinVar VariationId 1142046, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

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>G p.Val127Gly	missense	Exon 3 of 3	Prot: NP_000509.1 UniProt:

HBB NM_000518.5

MANE Select

HGVSc / HGVSpc.380T>Gp.Val127Gly

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>G p.Val127Gly	missense	Exon 3 of 3	Prot: ENSP00000333994.3 UniProt:
	HBB ENST00000647020.1		c.380T>G p.Val127Gly	missense	Exon 3 of 3	Prot: ENSP00000494175.1 UniProt:
	HBB ENST00000883533.1		c.380T>G p.Val127Gly	missense	Exon 4 of 4	Prot: ENSP00000553592.1 UniProt:

HBB ENST00000335295.4

TSL:1MANE Select

HGVSc / HGVSpc.380T>Gp.Val127Gly

Exon rankExon 3 of 3

missense

Prot: ENSP00000333994.3UniProt: P68871

HBB ENST00000647020.1

HGVSc / HGVSpc.380T>Gp.Val127Gly

Exon rankExon 3 of 3

missense

Prot: ENSP00000494175.1UniProt: P68871

HBB ENST00000883533.1

HGVSc / HGVSpc.380T>Gp.Val127Gly

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: 0.00000205	AC:3	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)	0.0000238	1	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: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	beta Thalassemia (2)
1	1	-	Beta-thalassemia HBB/LCRB (2)
1	-	-	Beta thalassemia intermedia (1)
1	-	-	Hemoglobinopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.21	N
FuncVEP CTI	Pathogenic	0.74
GPN-Star LLR	N/A	-4.7
GPN-Star score	N/A	4.7
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.27	D
Mutation Taster	N/A	2/98	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.9	H
PhyloP100	Benign	0.022
popEVE	Benign	-3.8
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Varity_R	N/A	0.50
VESM-3B	Benign	-9.2

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