11-5248439-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP6_ModerateBS2

The NM_000559.3(HBG1):c.364G>A(p.Glu122Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1O:2

Conservation

PhyloP100: 3.03

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

BP6

Variant 11-5248439-C-T is Benign according to our data. Variant chr11-5248439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 15023.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBG1	NM_000559.3 linkuse as main transcript	c.364G>A	p.Glu122Lys	missense_variant	3/3	ENST00000330597.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBG1	ENST00000330597.5 linkuse as main transcript	c.364G>A	p.Glu122Lys	missense_variant	3/3	1	NM_000559.3	P1
HBG1	ENST00000632727.1 linkuse as main transcript	c.*233G>A		3_prime_UTR_variant	3/3	3
HBG1	ENST00000648735.1 linkuse as main transcript	n.1295G>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251182

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1Other:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fetal hemoglobin quantitative trait locus 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 21, 2021

- -

HEMOGLOBIN F (HULL)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2011

- -

HEMOGLOBIN F (SIENA)

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Uncertain

0.090

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Benign

-0.021

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.96

D;D;T

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.77

D;D;D

MetaSVM

Uncertain

0.46

MutationTaster

Benign

0.51

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0040

D;.;.

Sift4G

Benign

0.14

T;.;.

Polyphen

0.97

D;.;.

Vest4

0.30

MVP

0.94

MPC

1.9

ClinPred

0.64

GERP RS

1.6

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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