rs28933078

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP3BP6_Moderate

The NM_000184.3(HBG2):c.178A>G(p.Lys60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K60Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HBG2
NM_000184.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 2.75

Publications

2 publications found

Variant links:

Genes affected

HBG2 (HGNC:4832): (hemoglobin subunit gamma 2) The gamma globin genes (HBG1 and HBG2) are normally expressed in the fetal liver, spleen and bone marrow. Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is normally replaced by adult hemoglobin (HbA) at birth. In some beta-thalassemias and related conditions, gamma chain production continues into adulthood. The two types of gamma chains differ at residue 136 where glycine is found in the G-gamma product (HBG2) and alanine is found in the A-gamma product (HBG1). The former is predominant at birth. 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]

HBG2 Gene-Disease associations (from GenCC):

hemoglobinopathy Toms River
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cyanosis, transient neonatal
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HBG2 links:

ENSG00000284931 (HGNC:):

ENSG00000284931 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000184.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

BP6

Variant 11-5254429-T-C is Benign according to our data. Variant chr11-5254429-T-C is described in CliVar as Likely_benign. Clinvar id is 14997.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5254429-T-C is described in CliVar as Likely_benign. Clinvar id is 14997.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5254429-T-C is described in CliVar as Likely_benign. Clinvar id is 14997.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5254429-T-C is described in CliVar as Likely_benign. Clinvar id is 14997.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5254429-T-C is described in CliVar as Likely_benign. Clinvar id is 14997.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3 link	c.178A>G	p.Lys60Glu	missense_variant	Exon 2 of 3	ENST00000336906.6	NP_000175.1	P69892D9YZU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBG2	ENST00000336906.6 link	c.178A>G	p.Lys60Glu	missense_variant	Exon 2 of 3	1	NM_000184.3	ENSP00000338082.4	P69892
ENSG00000284931	ENST00000642908.1 link	c.178A>G	p.Lys60Glu	missense_variant	Exon 2 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7 link	n.*1481A>G		non_coding_transcript_exon_variant	Exon 8 of 8	5		ENSP00000369609.3	A0A2U3TZJ3
ENSG00000239920	ENST00000380259.7 link	n.*1481A>G		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000369609.3	A0A2U3TZJ3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152274

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251458

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.305

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74394

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41480

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68054

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb F-Emirates variant (HBG2: c.178A>G;p.Lys60Glu, also known as Lys59Glu when numbered from the mature protein, rs28933078, HbVar ID: 600, ClinVar ID: 14997) is reported in the literature in an individual with no hematological findings. This variant is found in the non-Finnish European population with an overall allele frequency of 0.002% (2/113,742 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.512). Based on available information, this variant is considered to be likely benign References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html -

HEMOGLOBIN F (EMIRATES)

Other:1

Aug 05, 2011

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

0.34

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

.;.;T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.0

.;.;M;.

PhyloP100

2.8

PROVEAN

Uncertain

-2.7

.;.;D;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.0020

.;.;D;.

Sift4G

Uncertain

0.024

.;.;D;.

Polyphen

0.19

.;.;B;.

Vest4

0.46

MutPred

0.65

Loss of methylation at K60 (P = 0.0101);Loss of methylation at K60 (P = 0.0101);Loss of methylation at K60 (P = 0.0101);.;

MVP

0.91

ClinPred

0.95

GERP RS

2.7

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

Varity_R

0.63

gMVP

0.65

Mutation Taster

=12/88

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over