11-5248393-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000559.3(HBG1):ā€‹c.410C>Gā€‹(p.Ala137Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 152,242 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A137S) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0065 ( 13 hom., cov: 30)
Exomes š‘“: 0.00086 ( 5 hom. )
Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.423
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008590221).
BP6
Variant 11-5248393-G-C is Benign according to our data. Variant chr11-5248393-G-C is described in ClinVar as [Benign]. Clinvar id is 478899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00648 (986/152242) while in subpopulation AFR AF= 0.0214 (890/41520). AF 95% confidence interval is 0.0203. There are 13 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High AC in GnomAd4 at 986 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBG1NM_000559.3 linkuse as main transcriptc.410C>G p.Ala137Gly missense_variant 3/3 ENST00000330597.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBG1ENST00000330597.5 linkuse as main transcriptc.410C>G p.Ala137Gly missense_variant 3/31 NM_000559.3 P1
HBG1ENST00000648735.1 linkuse as main transcriptn.1341C>G non_coding_transcript_exon_variant 2/2
HBG1ENST00000632727.1 linkuse as main transcript downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00646
AC:
982
AN:
152124
Hom.:
13
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0214
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00242
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000962
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000456
Gnomad OTH
AF:
0.00526
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000862
AC:
1259
AN:
1461064
Hom.:
5
Cov.:
34
AF XY:
0.000865
AC XY:
629
AN XY:
726848
show subpopulations
Gnomad4 AFR exome
AF:
0.0167
Gnomad4 AMR exome
AF:
0.00227
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.000605
Gnomad4 SAS exome
AF:
0.00193
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000289
Gnomad4 OTH exome
AF:
0.00139
GnomAD4 genome
AF:
0.00648
AC:
986
AN:
152242
Hom.:
13
Cov.:
30
AF XY:
0.00617
AC XY:
459
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.0214
Gnomad4 AMR
AF:
0.00242
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000964
Gnomad4 SAS
AF:
0.00249
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000456
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.0194
Hom.:
0
ExAC
AF:
0.0610
AC:
7401

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hereditary persistence of fetal hemoglobin Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 21, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
5.6
DANN
Benign
0.72
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.037
N
LIST_S2
Benign
0.39
T;T;T
MetaRNN
Benign
0.0086
T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.79
N;.;.
REVEL
Benign
0.20
Sift
Benign
1.0
T;.;.
Sift4G
Benign
0.56
T;.;.
Polyphen
0.0
B;.;.
Vest4
0.033
MPC
1.2
ClinPred
0.000022
T
GERP RS
1.7
gMVP
0.32

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

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

Other links and lift over

dbSNP: rs56205611; hg19: chr11-5269623; COSMIC: COSV57963391; COSMIC: COSV57963391; API