Genetic Variant HBG1:p.Asp74Asn (chr11-5249463-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_000559.3(HBG1):c.220G>A(p.Asp74Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/20 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. D74H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 10)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 0.267

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:

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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=0.12197623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.220G>A	p.Asp74Asn	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.220G>A	p.Asp74Asn	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-976G>A		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

798726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

404312

African (AFR)

AF:

0.00

AC:

AN:

18318

American (AMR)

AF:

0.00

AC:

AN:

31750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18180

East Asian (EAS)

AF:

0.00

AC:

AN:

31260

South Asian (SAS)

AF:

0.00

AC:

AN:

56770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2920

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

563758

Other (OTH)

AF:

0.00

AC:

AN:

36170

GnomAD4 genome

Cov.:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN F (FOREST PARK)

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

0.068

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.089

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.017

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.42

PhyloP100

0.27

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.6

REVEL

Benign

0.21

Sift

Benign

0.088

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.071

MutPred

0.54

Gain of MoRF binding (P = 0.044);

MVP

0.80

MPC

1.2

ClinPred

0.059

GERP RS

-0.53

PromoterAI

0.011

Neutral

(source)

gMVP

0.30

Mutation Taster

=42/58

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