11-5249789-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_000559.3(HBG1):c.16G>A(p.Glu6Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 5)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 2.02

Publications

3 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08145425).

BP6

Variant 11-5249789-C-T is Benign according to our data. Variant chr11-5249789-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 15024.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.16G>A	p.Glu6Lys	missense_variant	Exon 1 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.16G>A	p.Glu6Lys	missense_variant	Exon 1 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-1302G>A		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

28606

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

AF:

0.00000332

AC:

AN:

301650

Hom.:

Cov.:

AF XY:

0.00000628

AC XY:

AN XY:

159156

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000115

AC:

AN:

8664

American (AMR)

AF:

0.00

AC:

AN:

13886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8922

East Asian (EAS)

AF:

0.00

AC:

AN:

17944

South Asian (SAS)

AF:

0.00

AC:

AN:

36226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

178434

Other (OTH)

AF:

0.00

AC:

AN:

16630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

28606

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

12742

African (AFR)

AF:

0.00

AC:

AN:

5112

American (AMR)

AF:

0.00

AC:

AN:

2210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

740

East Asian (EAS)

AF:

0.00

AC:

AN:

1048

South Asian (SAS)

AF:

0.00

AC:

AN:

862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

122

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

15846

Other (OTH)

AF:

0.00

AC:

AN:

338

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary persistence of fetal hemoglobin

Benign:1

May 02, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HEMOGLOBIN F (TEXAS I)

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

Benign

0.084

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.70

T;.

M_CAP

Benign

0.025

MetaRNN

Benign

0.081

T;T

MetaSVM

Benign

-0.68

PhyloP100

2.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.39

N;.

REVEL

Benign

0.28

Sift

Uncertain

0.012

D;.

Sift4G

Benign

0.70

T;.

Polyphen

0.0020

B;.

Vest4

0.11

MutPred

0.60

Gain of ubiquitination at E6 (P = 0.0155);Gain of ubiquitination at E6 (P = 0.0155);

MVP

0.79

MPC

1.3

ClinPred

0.17

GERP RS

-1.1

PromoterAI

0.021

Neutral

(source)

gMVP

0.33

Mutation Taster

=40/60

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