chr11-5227003-C-T

Variant names:

• chr11-5227003-C-T
• rs33930165
• NM_000518.5:c.19G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 16P and 2B. PS3 PM1 PM5 PP5_Very_Strong BP4 BS2_Supporting

The NM_000518.5(HBB):​c.19G>A​(p.Glu7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,611,030 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001445885: Functional studies have shown that this variant reduces the overall hydrophobicity as compared to wild type hemoglobin (PMID:2888754)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35 B:1 O:1
• Conservation: PhyloP100: 2.63
• Publications: 120 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001445885: Functional studies have shown that this variant reduces the overall hydrophobicity as compared to wild type hemoglobin (PMID: 2888754).; SCV002097813: Functional studies have shown that this variant reduces the overall hydrophobicity as compared to wild type hemoglobin [PMID:2888754].; SCV006059874: Functional evidence demonstrates that the c.19G>A variant reduces the hydrophobicity of hemoglobin compared to wildtype (PMID: 2888754).; SCV000321759: Published functional studies demonstrate the E7K variant reduces the overall hydrophobicity as compared to wild type hemoglobin (Adachi et al., 1987); PMID: 8294201; SCV000930769: Experimental studies have shown that this missense change affects HBB function (PMID: 2888754).; SCV006325227: Functional studies indicate that the p.Glu7Lys sequence change results in reduced hydrophobicity versus wild-type hemoglobin (PMIDs: 2888754).; SCV001142415: Experimental studies have shown that this variant affects the kinetic properties of the hemoglobin protein (PMID: 2888754).; SCV002061274: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 15973412) - PS3_supporting."; SCV003839040: experimental studies have shown that this variant affects the physical and kinetic properties of the hemoglobin protein.; SCV004046376: Experimental studies showed that this variant affected the kinetic properties of the hemoglobin protein (PMID: 2888754).; SCV004847532: "In vitro functional studies provide some evidence that this variant affects the kinetic properties of the hemoglobin protein, reducing its overall hydrophobicity (Adachi 1987 PMID: 2888754)."
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 30 uncertain in NM_000518.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5227002-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 11-5227003-C-T is Pathogenic according to our data. Variant chr11-5227003-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01455009). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR,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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.19G>A	p.Glu7Lys	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.19G>A	p.Glu7Lys	missense	Exon 1 of 3	ENSP00000333994.3	P68871
	HBB	ENST00000485743.1	TSL:1	c.19G>A	p.Glu7Lys	missense	Exon 1 of 2	ENSP00000496200.1	A0A2R8Y7R2
	HBB	ENST00000647020.1		c.19G>A	p.Glu7Lys	missense	Exon 1 of 3	ENSP00000494175.1	P68871

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 570 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000916 AC: 230 AN: 251156 AF XY: 0.000567

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000422 AC: 615 AN: 1458696 Hom.: 6 Cov.: 33 AF XY: 0.000376 AC XY: 273 AN XY: 725878

African (AFR) AF: 0.0159 AC: 532 AN: 33368

American (AMR) AF: 0.000246 AC: 11 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1109158

Other (OTH) AF: 0.000896 AC: 54 AN: 60284

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00356 AC XY: 265 AN XY: 74508

African (AFR) AF: 0.0134 AC: 556 AN: 41568

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.00536

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00123 AC: 149

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	not provided (13)
5	-	-	Hb SS disease (6)
4	-	-	beta Thalassemia (4)
2	-	-	Beta-thalassemia HBB/LCRB (2)
2	-	-	HBB-related disorder (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	-	-	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	-	-	Heinz body anemia (1)
1	-	-	HEMOGLOBIN C (1)
1	-	-	Hereditary persistence of fetal hemoglobin (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Inherited hemoglobinopathy (1)
1	-	-	Sickle cell-hemoglobin C disease (1)
-	-	-	Malaria, resistance to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.015	D
Sift4G	Benign	0.41	T
Polyphen		0.0050	B
Vest4		0.83
MVP		0.95
MPC		0.037
ClinPred		0.046	T
GERP RS		5.2
PromoterAI		-0.033	Neutral
Varity_R		0.68
gMVP		0.52
Mutation Taster		=23/77	disease causing (ClinVar)

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: rs33930165; hg19: chr11-5248233;