rs121909818

chr11-5225714-C-Tchr11-5225714-C-Achr11-5225714-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000518.5(HBB):c.328G>A(p.Val110Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V110L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -0.202

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225714-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 15230.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 11-5225714-C-T is Pathogenic according to our data. Variant chr11-5225714-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29473293).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.328G>A	p.Val110Met	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.328G>A	p.Val110Met	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.328G>A	p.Val110Met	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.260G>A		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*144G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 26, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals and families affected with erythrocytosis (PMIDs: 1201208 (1975), 7204093 (1981), 6863429 (1983), 18818920 (2009), 23859443 (2013), and 27651169 (2016). This variant has also been shown to co-segregate with erythrocytosis (PMIDs: 18793248 (2009), 30423154 (2019), and 31304856 (2019)). This variant has also been shown to co-segregate with erythrocytosis (PMIDs: 18793248 (2009) and 30423154 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2023	The Hb San Diego variant (HBB: c.328G>A; p.Val110Met, also known as Val109Met when numbered from the mature protein, rs33969677) has been reported in a heterozygous state in multiple individuals with familial erythrocytosis (Bento 2013, Gonzalez Fernandez 2009, Nute 1974, HbVar database and references therein). It is listed in ClinVar (Variation ID: 15342), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The residue Val110 is within the alpha1beta2 contact zone, which is important for oxygen uptake and its related allosteric effects (Gonzalez Fernandez 2009). The valine at codon 110 is moderately conserved, and functional characterization of the variant hemoglobin demonstrates increased oxygen affinity (reduced P50), resulting in reduced oxygen release to the tissue (Chanarin 1975, Nute 1974). In addition, this variant has been shown to segregate with increased oxygen affinity (Nute 1974). An additional high oxygen affinity Hb variant at this position (Hb Johnstown: Val110Leu) has also been described in association with erythrocytosis (Feliu-Torres 2004). Based on available information, the Hb San Diego variant is considered pathogenic for familial erythrocytosis. REFERENCES Link to HbVar database for Hb San Diego: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=483 Bento C et al. Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?). Eur J Haematol. 2013; 91(4):361-8. Chanarin I et al. Erythraemia due to haemoglobin San Diego. Br J Haematol. 1975; 30(2):167-75. Feliu-Torres A et al. Hb Johnstown (beta109(G11)Val-->Leu): A high oxygen affinity variant associated with beta0-thalassemia. Hemoglobin. 2004;28(4):335-8. Gonzalez Fernandez F et al. Haemoglobinopathies with high oxygen affinity. Experience of Erythropathology Cooperative Spanish Group. Ann Hematol. 2009; 88(3):235-8. Nute P et al. Hemoglobinopathic erythrocytosis due to a new electrophoretically silent variant, hemoglobin San Diego (beta109 (G11)val--met). J Clin Invest. 1974;53(1):320-8. -

Erythrocytosis, familial, 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 16, 2021

Variant summary: HBB c.328G>A (p.Val110Met), also known as Hb San Diego, results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251212 control chromosomes. c.328G>A has been reported in the literature in multiple individuals and families affected with idopathic or familial erythrocytosis (Nute_1974, Rumi_2008, Bento_2013, Boster_2019, Camps_2016, Gonzalez Fernandez_2009, Xiong_2019). Additionally, the variant was reported to co-segregate with erythrocytosis in two- and three-generation families in an autosomal dominant manner (Gonzalez Fernandez_2009, Xiong_2019). These data indicate that the variant is very likely to be associated with familial erythrocytosis. P50 values were shown to be reduced in affected indviduals and family members (Nute_1974, Rumi_2008). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. To our knowledge, Hb San Diego has not been reported in the homozygous state, in combination with beta thalassemia or other beta globin variants, therefore its pathogenicity in regards to beta thalassemia is unknown. Based on the evidence outlined above, the variant was classified as pathogenic for erythrocytosis. -

beta Thalassemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Feb 17, 2015

- -

HEMOGLOBIN SAN DIEGO 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	Benign	0.25
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.058	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.086	N
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.85	N;.
REVEL	Uncertain	0.62
Sift	Benign	0.33	T;.
Sift4G	Benign	0.20	T;.
Polyphen		0.85	P;P
Vest4		0.39
MutPred		0.66		Loss of stability (P = 0.2717);Loss of stability (P = 0.2717);
MVP		0.67
MPC		0.045
ClinPred		0.24	T
GERP RS		0.68
Varity_R		0.18
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33969677; hg19: chr11-5246944;