Genetic Variant NM_000559.3:c.227C>G (chr11-5249456-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000559.3(HBG1):c.227C>G(p.Thr76Arg) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T76I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 9)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.53

Publications

25 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15724012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.227C>G	p.Thr76Arg	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.227C>G	p.Thr76Arg	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-969C>G		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

72926

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

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

AF:

0.00

AC:

AN:

758362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

383296

African (AFR)

AF:

0.00

AC:

AN:

17198

American (AMR)

AF:

0.00

AC:

AN:

27752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16738

East Asian (EAS)

AF:

0.00

AC:

AN:

30356

South Asian (SAS)

AF:

0.00

AC:

AN:

51940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37848

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

539448

Other (OTH)

AF:

0.00

AC:

AN:

34336

GnomAD4 genome

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

AF:

0.00

AC:

AN:

72996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34936

African (AFR)

AF:

0.00

AC:

AN:

18808

American (AMR)

AF:

0.00

AC:

AN:

6770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1920

East Asian (EAS)

AF:

0.00

AC:

AN:

2626

South Asian (SAS)

AF:

0.00

AC:

AN:

1844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

33232

Other (OTH)

AF:

0.00

AC:

AN:

894

Alfa

AF:

0.00

Hom.:

2145

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0086

MetaRNN

Benign

0.16

MetaSVM

Uncertain

-0.24

PhyloP100

4.5

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

REVEL

Benign

0.28

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.014

Vest4

0.34

MutPred

0.49

Gain of MoRF binding (P = 0.0343);

MVP

0.30

MPC

1.4

ClinPred

0.51

GERP RS

0.26

PromoterAI

-0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.84

Mutation Taster

=77/23

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over