rs372131208

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002049.4(GATA1):c.113C>T(p.Pro38Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0003 in 1,204,266 control chromosomes in the GnomAD database, including 1 homozygotes. There are 133 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 10 hem., cov: 22)

Exomes 𝑓: 0.00030 ( 1 hom. 123 hem. )

Consequence

GATA1
NM_002049.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.89

Publications

2 publications found

Variant links:

Genes affected

GATA1 (HGNC:4170): (GATA binding protein 1) This gene encodes a protein which belongs to the GATA family of transcription factors. The protein plays an important role in erythroid development by regulating the switch of fetal hemoglobin to adult hemoglobin. Mutations in this gene have been associated with X-linked dyserythropoietic anemia and thrombocytopenia. [provided by RefSeq, Jul 2008]

GATA1 Gene-Disease associations (from GenCC):

GATA1-Related X-Linked Cytopenia
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
thrombocytopenia, X-linked, with or without dyserythropoietic anemia
Inheritance: XL Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
beta-thalassemia-X-linked thrombocytopenia syndrome
Inheritance: XL Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
Diamond-Blackfan anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cutaneous porphyria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thrombocytopenia with congenital dyserythropoietic anemia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked dyserythropoetic anemia with abnormal platelets and neutropenia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GATA1 links:

ENSG00000232828 (HGNC:):

ENSG00000232828 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021208674).

BP6

Variant X-48791222-C-T is Benign according to our data. Variant chrX-48791222-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000322 (36/111933) while in subpopulation AMR AF = 0.000655 (7/10694). AF 95% confidence interval is 0.000306. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 10 AR,XL,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA1	NM_002049.4 link	c.113C>T	p.Pro38Leu	missense_variant	Exon 2 of 6	ENST00000376670.9	NP_002040.1	P15976-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9 link	c.113C>T	p.Pro38Leu	missense_variant	Exon 2 of 6	1	NM_002049.4	ENSP00000365858.3		P15976-1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

111877

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.000396

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.000489

AC:

AN:

167604

AF XY:

0.000490

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00126

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000232

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

AF:

0.000298

AC:

325

AN:

1092333

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

123

AN XY:

358687

show subpopulations

African (AFR)

AF:

0.0000759

AC:

AN:

26342

American (AMR)

AF:

0.00133

AC:

AN:

34526

Ashkenazi Jewish (ASJ)

AF:

0.00109

AC:

AN:

19193

East Asian (EAS)

AF:

0.00

AC:

AN:

30115

South Asian (SAS)

AF:

0.00108

AC:

AN:

52908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40148

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.000185

AC:

155

AN:

839115

Other (OTH)

AF:

0.000654

AC:

AN:

45873

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000322

AC:

AN:

111933

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

34099

show subpopulations

African (AFR)

AF:

0.0000649

AC:

AN:

30810

American (AMR)

AF:

0.000655

AC:

AN:

10694

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3524

South Asian (SAS)

AF:

0.00

AC:

AN:

2667

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6147

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000396

AC:

AN:

53005

Other (OTH)

AF:

0.00130

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000583

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000429

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 19, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GATA1 c.113C>T (p.Pro38Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 167604 control chromosomes in the gnomAD database, including 1 homozygote and multiple hemizygotes, suggesting it is likely a benign polymorphism. c.113C>T has been reported in the literature in individuals affected with GATA1-Related Disorders without strong evidence of causality (e.g. Lin_2024). These report(s) do not provide unequivocal conclusions about association of the variant with GATA1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 38103590). ClinVar contains an entry for this variant (Variation ID: 435275). Based on the evidence outlined above, the variant was classified as likely benign. -

GATA1-related disorder

Benign:1

Aug 29, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GATA1: BS2 -

Diamond-Blackfan anemia;C1845837:GATA binding protein 1 related thrombocytopenia with dyserythropoiesis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;T

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.021

T;T

MetaSVM

Uncertain

0.031

MutationAssessor

Benign

0.0

N;.

PhyloP100

5.9

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.83

N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.018

D;D

Sift4G

Benign

0.29

T;T

Polyphen

0.0020

B;.

Vest4

0.27

MVP

0.56

MPC

0.047

ClinPred

0.050

GERP RS

3.6

Varity_R

0.13

gMVP

0.41

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over