11-5225714-C-T

Variant names:

• chr11-5225714-C-T
• rs33969677
• NM_000518.5:c.328G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 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 (★★).

• 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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.328G>A	p.Val110Met	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.328G>A	p.Val110Met	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

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

Sep 26, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb San Diego variant (HBB: c.328G>A; p.Val110Met, also known as Val109Met in the mature protein, rs33969677, ClinVar Variant ID: 15342, HbVarID: 483) has been reported in the heterozygous state in multiple individuals with familial erythrocytosis (Bento 2013, Boster 2019, Camps 2016, Coleman 1993, Gonzalez Fernandez 2009, van Zwieten 2014, Xiong 2019). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.328G>C, p.Val110Leu and c.328G>T, p.Val110Leu) have been reported in individuals with familial erythrocytosis (Agarwal 2007, Inoue 2012, Jones 1990). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). However, functional analyses of the p.Val110Met variant protein show increased oxygen affinity (reduced P50), resulting in reduced oxygen release to the tissue (Anderson 1974, Harkness 1981, Nute 1974). Based on available information, the Hb San Diego variant is considered to be pathogenic. References: Agarwal N et al. Familial polycythemia caused by a novel mutation in the beta globin gene: essential role of P50 in evaluation of familial polycythemia. Int J Med Sci. 2007 Oct 4. PMID: 17952198 Anderson NL. Hemoglobin San Diego (beta 109 (G11) val--met). Crystal structure of the deoxy form. J Clin Invest. 1974 Jan. PMID: 4808645 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 Oct. PMID: 23859443 Boster J et al. Hemoglobin San Diego: An Uncommon Cause of Hereditary Erythrocytosis Discovered Incidentally in a Military Trainee. Mil Med. 2019 May 1. PMID: 30423154 Camps C et al. Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. Haematologica. 2016 Nov. PMID: 27651169 Coleman MB et al. Hb San Diego [beta 109(G11)Val-->Met] in an Iranian: further evidence for a mutational hot spot at position 109 of the beta-globin gene. Hemoglobin. 1993 Dec. PMID: 8144354 Gonzalez Fernandez FA et al. Haemoglobinopathies with high oxygen affinity. Experience of Erythropathology Cooperative Spanish Group. Ann Hematol. 2009 Mar. PMID: 18818920 Harkness DR et al. Novel studies on a "silent" high affinity mutant hemoglobin (San Diego, beta 109 Val replaced by Met). Hemoglobin. 1981 PMID: 7204093 Inoue S et al. Symptomatic erythrocytosis associated with a compound heterozygosity for Hb Lepore-Boston-Washington (delta87-beta116) and Hb Johnstown [beta109(G11)Val-->Leu, GTG>TTG]. Hemoglobin. 2012 PMID: 22563907 Jones RT et al. Hb Johnstown [beta 109 (G11) Val----Leu]: a new electrophoretically silent variant that causes erythrocytosis. Hemoglobin. 1990 PMID: 2272838 Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Nute PE et al. Hemoglobinopathic erythrocytosis due to a new electrophoretically silent variant, hemoglobin San Diego (beta109 (G11)val--met). J Clin Invest. 1974 Jan. PMID: 4808644 van Zwieten R et al. Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones. Hemoglobin. 2014 PMID: 24200101 Xiong H et al. First Description of Hb San Diego (HBB: c.328G>A) in a Chinese Family with Congenital Erythrocytosis. Hemoglobin. 2019 Mar. PMID: 31304856 -

Erythrocytosis, familial, 6 Pathogenic:1

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hemoglobinopathy Pathogenic:1

Jul 16, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 17, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

HEMOGLOBIN SAN DIEGO 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	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
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.4	L;L
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;