11-5249459-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000559.3(HBG1):c.224C>A(p.Ala75Asp) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 1 hom., cov: 10)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

Publications

0 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 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.224C>A	p.Ala75Asp	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.224C>A	p.Ala75Asp	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-972C>A		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.0000258

AC:

AN:

77574

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

789084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

399362

African (AFR)

AF:

0.00

AC:

AN:

18054

American (AMR)

AF:

0.00

AC:

AN:

29456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17532

East Asian (EAS)

AF:

0.00

AC:

AN:

31058

South Asian (SAS)

AF:

0.00

AC:

AN:

55358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2876

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

559874

Other (OTH)

AF:

0.00

AC:

AN:

35676

GnomAD4 genome

AF:

0.0000258

AC:

AN:

77574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

37490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19490

American (AMR)

AF:

0.00

AC:

AN:

7200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2024

East Asian (EAS)

AF:

0.00

AC:

AN:

2878

South Asian (SAS)

AF:

0.00

AC:

AN:

2062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

35464

Other (OTH)

AF:

0.00

AC:

AN:

952

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.224C>A (p.A75D) alteration is located in exon 2 (coding exon 2) of the HBG1 gene. This alteration results from a C to A substitution at nucleotide position 224, causing the alanine (A) at amino acid position 75 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

(source)

DANN

Benign

0.92

Eigen

Benign

0.086

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.94

PhyloP100

3.6

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.68

MutPred

0.72

Gain of disorder (P = 0.0498);

MVP

0.93

MPC

2.8

ClinPred

0.93

GERP RS

1.8

PromoterAI

0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.93

Mutation Taster

=27/73

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over