11-5225607-C-G

Position:

• chr11-5225607-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 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 same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K145E) 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 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 id is 15096.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.435G>C	p.Lys145Asn	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.435G>C	p.Lys145Asn	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.435G>C	p.Lys145Asn	missense_variant	3/3			P1
HBB	ENST00000633227.1	c.*251G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
HBB	ENST00000475226.1			downstream_gene_variant		2

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1978

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 06, 2021

The Hb Andrew-Minneapolis variant (HBB: c.435G>C; p.Lys145Asn, also known as Lys144Asn when numbered from the mature protein) (rs35020585) 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 present on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. The lysine at codon 145 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: .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 for Hb Andrew-Minneapolis: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=567 Gomi T et al. Hemoglobin Andrew-Minneapolis (beta 144 (HCl) lysine----asparagine) in a Japanese family. Intern Med. 1992 May;31(5):659-61. 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. Ropero P et al. Erythrocytosis in a child due to Hb Andrew-Minneapolis [ß144(HC1)Lys?Asn (AAG>AAT or AAC)] associated with a Spanish (dß)(0)-thalassemia. Hemoglobin. 2013;37(1):48-55. 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. -

HEMOGLOBIN ANDREW-MINNEAPOLIS Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

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
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs35020585; hg19: chr11-5246837;