rs104894815

Variant names:

• chrX-48792337-G-A
• rs104894815
• NM_002049.4:c.613G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_002049.4(GATA1):​c.613G>A​(p.Val205Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GATA1 NM_002049.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.12
• Publications: 30 publications found

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002049.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant X-48792337-G-A is Pathogenic according to our data. Variant chrX-48792337-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10423.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002049.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA1	NM_002049.4	MANE Select	c.613G>A	p.Val205Met	missense	Exon 4 of 6	NP_002040.1	P15976-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA1	ENST00000376670.9	TSL:1 MANE Select	c.613G>A	p.Val205Met	missense	Exon 4 of 6	ENSP00000365858.3	P15976-1
	GATA1	ENST00000696450.1		c.613G>A	p.Val205Met	missense	Exon 4 of 6	ENSP00000512637.1	A0A8Q3SIN3
	GATA1	ENST00000696452.1		c.364G>A	p.Val122Met	missense	Exon 3 of 5	ENSP00000512639.1	A0A8Q3SIT6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Thrombocytopenia, X-linked, with dyserythropoietic anemia (1)
-	-	-	Thrombocytopenia, X-linked, with or without dyserythropoietic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.67
MutPred		0.42		Gain of catalytic residue at V205 (P = 0.0063)
MVP		1.0
MPC		3.0
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.43
gMVP		0.72
Mutation Taster		=33/67	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894815; hg19: chrX-48650744;