rs33962676

Positions:

chr11-5226972-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000518.5(HBB):c.50G>A(p.Gly17Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1O:1

Conservation

PhyloP100: -0.178

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.50G>A	p.Gly17Asp	missense_variant	1/3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.50G>A	p.Gly17Asp	missense_variant	1/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251228

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000657

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2022	Reported in combination with either hemoblobin S, hemoglobin C, or beta thalassemia trait, but limited clinical information is provided on these individuals (Baglioni and Weatherall, 1963; Huisman et al., 1978; Musumeci et al., 1979; Arribalzaga et al., 1996); Observed in the heterozygous state in a mother and daughter with abnormally low HbA1c levels (Gargallo et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also described as Gly16Asp or Hb J-Baltimore using alternate nomenclature (Baglioni and Weatherall, 1963; Gargallo et al., 2010; Riou et al., 2015); This variant is associated with the following publications: (PMID: 27535164, 3808941, 14117783, 8226093, 5125343, 19429541, 31553106, 14092068, 511585, 24200101, 8745435, 19750260, 20206586, 25130136, 700140) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 05, 2024	The HBB c.50G>A (p.Gly17Asp) variant (also known as Hb J-Baltimore) has been reported in the heterozygous state in individuals with normal clinical presentation (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), and PMIDs: 26901597 (2015), 8745435 (1996), 8226093 (1993), 14117783 (1964)). Individuals who carry Hb J-Baltimore in combination with the Hb S (HBB c.20A>T, p.Glu7Val) or Hb C (HBB c.19G>A, p.Glu7Lys) pathogenic variant have clinical and hematological findings similar to carriers of Hb S or Hb C alone (PMID: 14117783 (1964)). Hb J-Baltimore is also reported to have normal stability (PMIDs: 8226093 (1993), 8745435 (1996)). The frequency of this variant in the general population, 0.000054 (7/129002 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 14, 2023

Variant summary: HBB c.50G>A (p.Gly17Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 1613680 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Hemoglobinopathy (4.9e-05 vs 0.011), allowing no conclusion about variant significance. The variant, c.50G>A, has been reported in the literature in multiple compound heterozygotes carrying the variant of interest and HbS (e.g. Weatherall_1964, Baglioni_1963, Huisman_1978), and at least 3 of these individuals has been stated to have no symptoms suggestive of anemia or sickle-cell crisis during several years of follow up (Weatherall_1964). A functional study, which measured the rate of change of blood viscosity during deoxygenation demonstrated that blood from a compound heterozygote, behaved similarly to that of sickle-cell carriers, i.e. the variant didn't contribute to sickling (Weatherall_1964, Charache_1964). The variant also has been reported in at least 3 compound heterozygotes who carried a beta-thalassemia allele (Musumeci_1979, Arribalzaga_1996), these individuals had hematological parameters largely similar to individuals with beta-thalassemia trait. Functional studies performed on samples from two of these individuals, indicated normal oxyhemoglobin dissociation curves and P50 values, similar to thalassemia carriers (Arribalzaga_1996). Other functional studies noted no Heinz-body formation, or instability, in addition, oxygen affinity, Bohr-effect, and cooperativity, were all noted to be similar to normal (e.g. Musumeci_1979, Arribalzaga_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8745435, 14092068, 14194270, 20206586, 19429541, 6859036, 700140, 16178917, 19750260, 5481775, 14282052, 3957922, 511585, 31553106, 17709689, 14117783). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=1) ans VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

HEMOGLOBIN J (BALTIMORE)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jan 01, 1979

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

T;T;.;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.75

.;T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.72

D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

2.0

M;M;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

D;.;.;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.013

D;.;.;D

Sift4G

Benign

0.13

T;.;.;.

Polyphen

0.0080

B;B;.;.

Vest4

0.86

MutPred

0.74

Loss of methylation at K18 (P = 0.0744);Loss of methylation at K18 (P = 0.0744);Loss of methylation at K18 (P = 0.0744);Loss of methylation at K18 (P = 0.0744);

MVP

0.77

MPC

0.044

ClinPred

0.16

GERP RS

1.1

Varity_R

0.49

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over