11-5226943-C-T

Variant names:

• chr11-5226943-C-T
• rs33950507
• NM_000518.5:c.79G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM5 PP3 PP5_Very_Strong BS2_Supporting

The NM_000518.5(HBB):​c.79G>A​(p.Glu27Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,613,724 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E27D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (5 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:36 B:1 O:3
• Conservation: PhyloP100: 1.15
• Publications: 223 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, 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), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 34 uncertain in NM_000518.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226941-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 599394.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-5226943-C-T is Pathogenic according to our data. Variant chr11-5226943-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 15161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.79G>A	p.Glu27Lys	missense	Exon 1 of 3	NP_000509.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	ENST00000335295.4	TSL:1 MANE Select	c.79G>A	p.Glu27Lys	missense	Exon 1 of 3	ENSP00000333994.3
	HBB	ENST00000485743.1	TSL:1	c.79G>A	p.Glu27Lys	missense	Exon 1 of 2	ENSP00000496200.1
	HBB	ENST00000647020.1		c.79G>A	p.Glu27Lys	missense	Exon 1 of 3	ENSP00000494175.1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000255 AC: 64 AN: 251352 AF XY: 0.000317

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000204 AC: 298 AN: 1461396 Hom.: 5 Cov.: 33 AF XY: 0.000275 AC XY: 200 AN XY: 727050

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39690

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111578

Other (OTH) AF: 0.00113 AC: 68 AN: 60378

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74486

African (AFR) AF: 0.000120 AC: 5 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5180

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
6	-	-	beta Thalassemia (6)
6	-	-	Beta-thalassemia HBB/LCRB (6)
2	-	-	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 (2)
2	-	-	Hemoglobin E disease (2)
1	-	-	alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6 (1)
1	-	-	alpha Thalassemia;C0002895:Hb SS disease;C0700299:Heinz body anemia;C1858990:Dominant beta-thalassemia;CN322236:Beta-thalassemia HBB/LCRB (1)
1	-	-	Anemia (1)
1	-	-	Beta-plus-thalassemia (1)
1	-	-	Hb SS disease (2)
1	-	-	HBB-related disorder (1)
1	-	-	Hemoglobin E/beta thalassemia disease (1)
1	-	-	Hemoglobin E/beta- thalassemia (1)
1	-	-	Hereditary persistence of fetal hemoglobin (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.020	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.025	D
Sift4G	Benign	0.15	T
Polyphen		0.72	P
Vest4		0.83
MVP		0.92
MPC		0.060
ClinPred		0.15	T
GERP RS		4.3
PromoterAI		0.066	Neutral
Varity_R		0.59
gMVP		0.78
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 3

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

Other links and lift over

dbSNP: rs33950507; hg19: chr11-5248173;