11-5225648-G-C

Variant names:

• chr11-5225648-G-C
• rs33910209
• NM_000518.5:c.394C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000518.5(HBB):​c.394C>G​(p.Gln132Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,782 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q132K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:3
• Conservation: PhyloP100: 3.69

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]

ENSG00000285498 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225646-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.32742304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.394C>G	p.Gln132Glu	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.394C>G	p.Gln132Glu	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jul 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.394C>G (p.Gln132Glu) variant has been reported in the published literature in individuals described as reportedly healthy individuals (PMIDs: 4550044 (1973), 808079 (1975)), suspected of anemia and/or hemoglobinopathy (PMIDs: 20309827 (2010), 24200101 (2014), 26635043 (2016)), or affected with alpha thalassemia (PMID: 7357091 (1980)). Functional studies have reported this variant to have normal stability and normal oxygen affinity (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter) and PMID: 4550044 (1973)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant. -

Aug 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Camden variant (HBB: c.394C>G; p.Gln132Glu, also known as Gln131Glu when numbered from the mature protein, rs33910209, HbVar ID: 535), is a stable hemoglobin variant with normal oxygen affinity and has not been associated with any significant clinical symptoms in the heterozygote state or when identified in trans with Hb S (see HbVar link, Blackwell 1975, Cohen 1973). Additionally, Hb Camden has been identified in an individual with Hb S trait and alpha thal trait and is reported to be functionally equivalent to Hb A (Honig 1980). This variant is reported in ClinVar (Variation ID: 439160). This variant is also absent from the Genome Aggregation Database indicating it is not a common polymorphism. The glutamine at codon 132 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.560). Based on available information, the Hb Camden variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Blackwell RQ et al. Double heterozygosity for hemoglobin Camden (beta 131 Gln yields Glu) and hemoglobin S in an American negro. Vox Sang. 1975 28(1):50-6. Cohen PT et al. Letter: Amino-acid substitution in the alpha 1 beta 1 intersubunit contact of haemoglobin-Camden beta 131 (h9) g1n leads to g1u. Nature. 1973 243(5408):467-8. Honig GR et al. Two new sickle cell syndromes: HbS, Hb Camden, and alpha-thalassemia; and HbS in combination with Hb Tacoma. Blood. 1980 55(4):655-60. -

not specified Uncertain:1

Oct 10, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.394C>G (p.Gln132Glu) results in a conservative amino acid change located in the Globin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277032 control chromosomes (gnomAD). The variant, c.394C>G, has been reported in the literature in asymptomatic individuals and individuals affected with mild Hemoglobinopathy. These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. The functional properties of Hb-Camden in the heterozygous state appear to be normal, oxygen affinity appears to be normal, and no abnormalities in haem-haem interaction or Bohr shift was detected (Cohen_1973). However, other variants at this position have been reported as associated with B-thalassemia (c.394C>T, c.394C>A; Ithanet database), suggesting the codon might be important for gene function. To our knowledge, no other experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

HEMOGLOBIN MOTOWN Other:1

Apr 01, 1980

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN TOKUCHI Other:1

Apr 01, 1980

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN CAMDEN Other:1

Apr 01, 1980

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	0.15
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	0.064
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	.;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.56
Sift	Benign	0.051	T;.
Sift4G	Benign	0.28	T;.
Polyphen		0.015	B;B
Vest4		0.45
MutPred		0.63		Loss of catalytic residue at Q132 (P = 0.0952);Loss of catalytic residue at Q132 (P = 0.0952);
MVP		0.96
MPC		0.041
ClinPred		0.63	D
GERP RS		4.7
Varity_R		0.43
gMVP		0.67

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: rs33910209; hg19: chr11-5246878;