11-5225607-C-G

Variant names:

• chr11-5225607-C-G
• rs35020585
• NM_000518.5:c.435G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_000518.5(HBB):​c.435G>C​(p.Lys145Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K145M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.119
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 23 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5225607-C-G is Pathogenic according to our data. Variant chr11-5225607-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15096.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.435G>C	p.Lys145Asn	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.435G>C	p.Lys145Asn	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Erythrocytosis, familial, 6 Pathogenic:1

Sep 01, 1978

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Andrew-Minneapolis variant (HBB: c.435G>C; p.Lys145Asn, also known as Lys144Asn when numbered from the mature protein, rs35020585, HbVar ID: 567) is reported in the literature in multiple individuals with familial erythrocytosis, in both the heterozygous and homozygous states (Gomi 1992, Mehta 2017, Ropero 2013, Zak 1974, HbVar and references therein). In one case, this variant was reported to occur de novo, in trans to a large deletion, in an individual with marked erythrocytosis (Ropero 2013). This variant is absent from Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.508), however functional studies demonstrate increased oxygen affinity of the variant protein (Zak 1974, HbVar and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Gomi T et al. Hemoglobin Andrew-Minneapolis (beta 144 (HCl) lysine----asparagine) in a Japanese family. Intern Med. 1992 May;31(5):659-61. PMID: 1504431. Mehta P et al. Identification of high oxygen affinity hemoglobin (Hb Andrew-Minneapolis) in an Indian family. Int J Lab Hematol. 2017 Apr;39(2):e51-e54. PMID: 28042696. Ropero P et al. Erythrocytosis in a child due to Hb Andrew-Minneapolis [beta144(HC1)Lys?Asn (AAG>AAT or AAC)] associated with a Spanish (delta beta)(0)-thalassemia. Hemoglobin. 2013;37(1):48-55. PMID: 23215953. Zak SJ et al. Hemoglobin Andrew-Minneapolis alpha 2 A beta 2 144 Lys leads to Asn: a new high-oxygen-affinity mutant human hemoglobin. Blood. 1974 Oct;44(4):543-9. PMID: 4413656. -

HEMOGLOBIN ANDREW-MINNEAPOLIS Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	3.4	M;M
PhyloP100		0.12
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.020	D;.
Polyphen		0.057	B;B
Vest4		0.76
MutPred		0.42		Loss of ubiquitination at K145 (P = 0.0081);Loss of ubiquitination at K145 (P = 0.0081);
MVP		0.91
MPC		0.038
ClinPred		0.78	D
GERP RS		-2.8
Varity_R		0.61
gMVP		0.95
Mutation Taster		=1/99	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: rs35020585; hg19: chr11-5246837;