chr11-5249456-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000559.3(HBG1):c.227C>T(p.Thr76Ile) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 14806 hom., cov: 9)

Exomes 𝑓: 0.34 ( 115673 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 4.53

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 links:

ENSG00000284931 (HGNC:):

ENSG00000284931 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049443543).

BP6

Variant 11-5249456-G-A is Benign according to our data. Variant chr11-5249456-G-A is described in ClinVar as [Benign]. Clinvar id is 15005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5249456-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.227C>T	p.Thr76Ile	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>T	p.Thr76Ile	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-969C>T		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

38672

AN:

67888

Hom.:

14771

Cov.:

FAILED QC

Gnomad AFR

AF:

0.724

Gnomad AMI

AF:

0.525

Gnomad AMR

AF:

0.637

Gnomad ASJ

AF:

0.673

Gnomad EAS

AF:

0.818

Gnomad SAS

AF:

0.520

Gnomad FIN

AF:

0.391

Gnomad MID

AF:

0.720

Gnomad NFE

AF:

0.473

Gnomad OTH

AF:

0.591

GnomAD3 exomes

AF:

0.357

AC:

44146

AN:

123722

Hom.:

21892

AF XY:

0.338

AC XY:

22220

AN XY:

65650

show subpopulations

Gnomad AFR exome

AF:

0.702

Gnomad AMR exome

AF:

0.495

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.731

Gnomad SAS exome

AF:

0.333

Gnomad FIN exome

AF:

0.0679

Gnomad NFE exome

AF:

0.247

Gnomad OTH exome

AF:

0.410

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.339

AC:

241675

AN:

713244

Hom.:

115673

Cov.:

AF XY:

0.351

AC XY:

126461

AN XY:

360300

show subpopulations

Gnomad4 AFR exome

AF:

0.693

Gnomad4 AMR exome

AF:

0.565

Gnomad4 ASJ exome

AF:

0.610

Gnomad4 EAS exome

AF:

0.820

Gnomad4 SAS exome

AF:

0.498

Gnomad4 FIN exome

AF:

0.375

Gnomad4 NFE exome

AF:

0.256

Gnomad4 OTH exome

AF:

0.465

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.570

AC:

38747

AN:

67956

Hom.:

14806

Cov.:

AF XY:

0.556

AC XY:

18022

AN XY:

32404

show subpopulations

Gnomad4 AFR

AF:

0.724

Gnomad4 AMR

AF:

0.639

Gnomad4 ASJ

AF:

0.673

Gnomad4 EAS

AF:

0.819

Gnomad4 SAS

AF:

0.519

Gnomad4 FIN

AF:

0.391

Gnomad4 NFE

AF:

0.473

Gnomad4 OTH

AF:

0.598

Alfa

AF:

0.648

Hom.:

2145

ExAC

AF:

0.290

AC:

20785

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary persistence of fetal hemoglobin

Benign:1

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HBG1 POLYMORPHISM

Benign:1

Jan 01, 1985

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN F (SARDINIA)

Other:1

Mar 25, 2021

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

Benign

0.077

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.5

DANN

Benign

0.59

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.66

PrimateAI

Benign

0.37

PROVEAN

Benign

3.2

REVEL

Benign

0.23

Sift

Benign

0.61

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.050

MPC

1.3

ClinPred

0.0043

GERP RS

0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.36

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over