chr11-5249442-C-T

Variant names:

Variant summary

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

The NM_000559.3(HBG1):c.241G>A(p.Asp81Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D81Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000022 ( 1 hom., cov: 12)

Exomes 𝑓: 0.0000099 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: -0.946

Publications

2 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=0.09425071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.241G>A	p.Asp81Asn	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.241G>A	p.Asp81Asn	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-955G>A		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.0000223

AC:

AN:

89528

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:

0.000589

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: AS_VQSR

AF:

0.00000991

AC:

AN:

807330

Hom.:

Cov.:

AF XY:

0.00000976

AC XY:

AN XY:

409884

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19028

American (AMR)

AF:

0.00

AC:

AN:

30950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18442

East Asian (EAS)

AF:

0.000253

AC:

AN:

31578

South Asian (SAS)

AF:

0.00

AC:

AN:

58034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2962

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

568578

Other (OTH)

AF:

0.00

AC:

AN:

36314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.663

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000223

AC:

AN:

89528

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

43306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23334

American (AMR)

AF:

0.00

AC:

AN:

8574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2362

East Asian (EAS)

AF:

0.000589

AC:

AN:

3394

South Asian (SAS)

AF:

0.00

AC:

AN:

2316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

40284

Other (OTH)

AF:

0.00

AC:

AN:

1130

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN F (YAMAGUCHI)

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

0.083

BayesDel_addAF

Benign

0.0074

BayesDel_noAF

Benign

-0.23

CADD

Benign

5.9

(source)

DANN

Benign

0.76

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.80

M_CAP

Benign

0.038

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.55

PhyloP100

-0.95

PrimateAI

Benign

0.40

PROVEAN

Benign

0.86

REVEL

Uncertain

0.30

Sift

Benign

1.0

Sift4G

Benign

0.90

Polyphen

0.0020

Vest4

0.060

MutPred

0.56

Loss of ubiquitination at K83 (P = 0.0853);

MVP

0.56

MPC

1.2

ClinPred

0.014

GERP RS

-2.6

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.39

Mutation Taster

=48/52

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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chr11-5249442-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over