11-5248439-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3BP6_Moderate

The NM_000559.3(HBG1):​c.364G>A​(p.Glu122Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,870 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 (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

HBG1
NM_000559.3 missense

Scores

2
8
7

Clinical Significance

Likely benign criteria provided, single submitter B:1O:2

Conservation

PhyloP100: 3.03

Publications

2 publications found
Variant links:
Genes affected
HBG1 (HGNC:4831): (hemoglobin subunit gamma 1) 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]
HBG1 Gene-Disease associations (from GenCC):
  • hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • delta-beta-thalassemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.772
BP6
Variant 11-5248439-C-T is Benign according to our data. Variant chr11-5248439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 15023.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBG1NM_000559.3 linkc.364G>A p.Glu122Lys missense_variant Exon 3 of 3 ENST00000330597.5 NP_000550.2 P69891D9YZU8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBG1ENST00000330597.5 linkc.364G>A p.Glu122Lys missense_variant Exon 3 of 3 1 NM_000559.3 ENSP00000327431.4 P69891
ENSG00000284931ENST00000642908.1 linkc.364G>A p.Glu122Lys missense_variant Exon 3 of 3 ENSP00000495346.1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152088
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000358
AC:
9
AN:
251182
AF XY:
0.0000442
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:
0.0000793
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000445
AC:
65
AN:
1461782
Hom.:
0
Cov.:
34
AF XY:
0.0000316
AC XY:
23
AN XY:
727196
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000576
AC:
64
AN:
1111920
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000526
AC:
8
AN:
152088
Hom.:
0
Cov.:
30
AF XY:
0.0000673
AC XY:
5
AN XY:
74300
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41362
American (AMR)
AF:
0.00
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1Other:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Fetal hemoglobin quantitative trait locus 1 Benign:1
Oct 21, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

HEMOGLOBIN F (HULL) Other:1
Jul 15, 2011
OMIM
Significance:other
Review Status:no assertion criteria provided
Collection Method:literature only

- -

HEMOGLOBIN F (SIENA) Other:1
Jul 15, 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
0.098
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Benign
-0.021
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.96
D;D;T
M_CAP
Benign
0.031
D
MetaRNN
Pathogenic
0.77
D;D;D
MetaSVM
Uncertain
0.46
D
PhyloP100
3.0
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-2.6
D;.;.
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0040
D;.;.
Sift4G
Benign
0.14
T;.;.
Polyphen
0.97
D;.;.
Vest4
0.30
MVP
0.94
MPC
1.9
ClinPred
0.64
D
GERP RS
1.6
gMVP
0.48
Mutation Taster
=48/52
disease causing

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

Other links and lift over

dbSNP: rs33963857; hg19: chr11-5269669; COSMIC: COSV57963060; COSMIC: COSV57963060; API