dbSNP rs2402330: HBG1:c.*124T>A (chr11-5248235-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000559.3(HBG1):c.*124T>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,327,264 control chromosomes in the GnomAD database, including 922 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.046 ( 495 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 427 hom. )

Consequence

HBG1
NM_000559.3 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.268

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.*124T>A		downstream_gene_variant		ENST00000330597.5	NP_000550.2	P69891D9YZU8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5 link	c.*124T>A		downstream_gene_variant		1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.*124T>A		downstream_gene_variant				ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.0461

AC:

7008

AN:

152182

Hom.:

496

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.0263

GnomAD4 exome

AF:

0.00508

AC:

5964

AN:

1174964

Hom.:

427

Cov.:

AF XY:

0.00441

AC XY:

2616

AN XY:

593352

show subpopulations

African (AFR)

AF:

0.175

AC:

4664

AN:

26624

American (AMR)

AF:

0.00806

AC:

304

AN:

37704

Ashkenazi Jewish (ASJ)

AF:

0.00330

AC:

AN:

23362

East Asian (EAS)

AF:

0.00

AC:

AN:

37126

South Asian (SAS)

AF:

0.000226

AC:

AN:

75070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51002

Middle Eastern (MID)

AF:

0.00706

AC:

AN:

5098

European-Non Finnish (NFE)

AF:

0.000351

AC:

305

AN:

868518

Other (OTH)

AF:

0.0111

AC:

561

AN:

50460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

264

527

791

1054

1318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.0461

AC:

7015

AN:

152300

Hom.:

495

Cov.:

AF XY:

0.0444

AC XY:

3304

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.161

AC:

6685

AN:

41530

American (AMR)

AF:

0.0150

AC:

229

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68032

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

314

628

942

1256

1570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0376

Hom.:

Bravo

AF:

0.0586

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.082

(source)

DANN

Benign

0.17

PhyloP100

-0.27

Mutation Taster

=98/2

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over