dbSNP rs35746147: HBG1:p.Ala54Val (chr11-5249522-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000559.3(HBG1):c.161C>T(p.Ala54Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A54D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 8)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBG1
NM_000559.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.35

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3 link	c.161C>T	p.Ala54Val	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.161C>T	p.Ala54Val	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4		P69891
ENSG00000284931	ENST00000642908.1 link	c.316-1035C>T		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes

AF:

0.0000152

AC:

AN:

65772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000606

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000109

AC:

AN:

915718

Hom.:

Cov.:

AF XY:

0.00000216

AC XY:

AN XY:

462992

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21600

American (AMR)

AF:

0.00

AC:

AN:

36622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21244

East Asian (EAS)

AF:

0.00

AC:

AN:

33934

South Asian (SAS)

AF:

0.00

AC:

AN:

64872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3416

European-Non Finnish (NFE)

AF:

0.00000153

AC:

AN:

651802

Other (OTH)

AF:

0.00

AC:

AN:

40832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000152

AC:

AN:

65772

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

31378

show subpopulations

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

African (AFR)

AF:

0.0000606

AC:

AN:

16514

American (AMR)

AF:

0.00

AC:

AN:

5778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1656

East Asian (EAS)

AF:

0.00

AC:

AN:

2352

South Asian (SAS)

AF:

0.00

AC:

AN:

1760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

30408

Other (OTH)

AF:

0.00

AC:

AN:

776

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.79

MetaSVM

Pathogenic

1.0

PhyloP100

4.3

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.13

MutPred

0.90

Loss of disorder (P = 0.068);

MVP

0.99

MPC

2.3

ClinPred

0.98

GERP RS

2.8

PromoterAI

-0.037

Neutral

(source)

gMVP

0.23

Mutation Taster

=39/61

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over