Genetic Variant HBG1:p.His98Arg (chr11-5249390-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000559.3(HBG1):c.293A>G(p.His98Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H98L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000096 ( 0 hom., cov: 15)

Exomes 𝑓: 0.000010 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 1.64

Publications

1 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

HBG1 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.293A>G	p.His98Arg	missense_variant	Exon 2 of 3	ENST00000330597.5	NP_000550.2	P69891D9YZU8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5 link	c.293A>G	p.His98Arg	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-903A>G		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.00000961

AC:

AN:

104078

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:

0.0000216

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000871

AC:

AN:

229564

AF XY:

0.0000161

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:

0.0000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000104

AC:

AN:

1156038

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

580648

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:

26646

American (AMR)

AF:

0.00

AC:

AN:

41722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23152

East Asian (EAS)

AF:

0.00

AC:

AN:

35894

South Asian (SAS)

AF:

0.00

AC:

AN:

75794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4688

European-Non Finnish (NFE)

AF:

0.0000141

AC:

AN:

852440

Other (OTH)

AF:

0.00

AC:

AN:

48416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002759), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000961

AC:

AN:

104078

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

50538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28174

American (AMR)

AF:

0.00

AC:

AN:

10172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2676

East Asian (EAS)

AF:

0.00

AC:

AN:

3940

South Asian (SAS)

AF:

0.00

AC:

AN:

2722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

46216

Other (OTH)

AF:

0.00

AC:

AN:

1288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN F (DICKINSON)

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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

0.10

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.85

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.51

MetaSVM

Uncertain

0.45

PhyloP100

1.6

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.2

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Benign

0.29

Polyphen

0.94

Vest4

0.19

MVP

0.95

MPC

2.1

ClinPred

0.99

GERP RS

2.2

PromoterAI

0.026

Neutral

(source)

gMVP

0.50

Mutation Taster

=56/44

polymorphism

(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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chr11-5249390-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over