11-5225662-A-G

Variant names:

• chr11-5225662-A-G
• rs33925391
• NM_000518.5:c.380T>C
• HBB p.Val127Ala

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 (ACMG Germline Pathogenicity v2019). PM1PM2PM5BP6

The NM_000518.5(HBB):c.380T>C (p.Val127Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000744 (AC=12) in the gnomAD database across 1,613,952 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000219. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). 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.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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O: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: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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 = 0.0000219 — 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.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)
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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>C p.Val127Ala	missense	Exon 3 of 3	Prot: NP_000509.1 UniProt:

HBB NM_000518.5

MANE Select

HGVSc / HGVSpc.380T>Cp.Val127Ala

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>C p.Val127Ala	missense	Exon 3 of 3	Prot: ENSP00000333994.3 UniProt:
	HBB ENST00000647020.1		c.380T>C p.Val127Ala	missense	Exon 3 of 3	Prot: ENSP00000494175.1 UniProt:
	HBB ENST00000883533.1		c.380T>C p.Val127Ala	missense	Exon 4 of 4	Prot: ENSP00000553592.1 UniProt:

HBB ENST00000335295.4

TSL:1MANE Select

HGVSc / HGVSpc.380T>Cp.Val127Ala

Exon rankExon 3 of 3

missense

Prot: ENSP00000333994.3UniProt: P68871

HBB ENST00000647020.1

HGVSc / HGVSpc.380T>Cp.Val127Ala

Exon rankExon 3 of 3

missense

Prot: ENSP00000494175.1UniProt: P68871

HBB ENST00000883533.1

HGVSc / HGVSpc.380T>Cp.Val127Ala

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152178	Cov:33
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251316	Cov:
GnomAD4 exome	AF: 0.00000753	AC:11	Hom:0	AN:1461774	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152178	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9622	0.00 *	0	10428
SCHEMA(Schizophrenia)	0.00000967	1	103366	0.0000217	4	184654

Showing 2 cohortsAllele 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
-	1	1	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 BEIRUT (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.6
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	3.5
DANN	Benign	0.72
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.21	N
FuncVEP CTI	Benign	0.033
GPN-Star LLR	N/A	-2.5
GPN-Star score	N/A	2.5
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.41	T
Mutation Taster	N/A	5/95	disease causing
MutationAssessor	Benign	1.1	L
PhyloP100	Benign	0.022
popEVE	Benign	-2.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.36
Sift	Benign	0.50	T
Sift4G	Benign	0.33	T
Varity_R	N/A	0.12
VESM-3B	Benign	-5.5

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