Variant 11-5249442-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09425071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBG1	NM_000559.3 linkuse as main transcript	c.241G>A	p.Asp81Asn	missense_variant	2/3	ENST00000330597.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBG1	ENST00000330597.5 linkuse as main transcript	c.241G>A	p.Asp81Asn	missense_variant	2/3	1	NM_000559.3	P1
HBG1	ENST00000632727.1 linkuse as main transcript	c.*110G>A		3_prime_UTR_variant	2/3	3
HBG1	ENST00000648735.1 linkuse as main transcript	n.292G>A		non_coding_transcript_exon_variant	2/2

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000223

AC:

AN:

89528

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

43306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000589

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN F (YAMAGUCHI)

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

0.083

BayesDel_addAF

Benign

0.0074

BayesDel_noAF

Benign

-0.23

Cadd

Benign

5.9

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

MutationTaster

Benign

1.0

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.39

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