11-5227018-C-T

Variant names:

• chr11-5227018-C-T
• rs33958358
• NM_000518.5:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BP6

The NM_000518.5(HBB):​c.4G>A​(p.Val2Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000624 in 1,443,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V2A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:1
• Conservation: PhyloP100: 3.94
• Publications: 8 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• erythrocytosis, familial, 6

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

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

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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
• delta-beta-thalassemia

  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:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 18 uncertain in NM_000518.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• BP6: Variant 11-5227018-C-T is Benign according to our data. Variant chr11-5227018-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15359.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.4G>A	p.Val2Met	missense	Exon 1 of 3	NP_000509.1	D9YZU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	ENST00000335295.4	TSL:1 MANE Select	c.4G>A	p.Val2Met	missense	Exon 1 of 3	ENSP00000333994.3	P68871
	HBB	ENST00000485743.1	TSL:1	c.4G>A	p.Val2Met	missense	Exon 1 of 2	ENSP00000496200.1	A0A2R8Y7R2
	HBB	ENST00000647020.1		c.4G>A	p.Val2Met	missense	Exon 1 of 3	ENSP00000494175.1	P68871

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251128 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000624 AC: 9 AN: 1443092 Hom.: 0 Cov.: 26 AF XY: 0.00000278 AC XY: 2 AN XY: 719252

African (AFR) AF: 0.00 AC: 0 AN: 33070

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000822 AC: 9 AN: 1094784

Other (OTH) AF: 0.00 AC: 0 AN: 59754

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	beta Thalassemia (2)
-	2	-	not specified (2)
-	-	1	not provided (1)
-	-	-	HEMOGLOBIN SOUTH FLORIDA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.82
Sift	Benign	0.089	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.71		Gain of glycosylation at P6 (P = 0.0852)
MVP		0.76
MPC		0.14
ClinPred		0.88	D
GERP RS		4.2
PromoterAI		0.048	Neutral
Varity_R		0.21
gMVP		0.78
Mutation Taster		=9/91	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

Other links and lift over

dbSNP: rs33958358; hg19: chr11-5248248;