10-125733522-A-G

Variant names:

• chr10-125733522-A-G
• NM_001202438.2:c.1247A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001202438.2(EDRF1):​c.1247A>G​(p.Lys416Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,276 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EDRF1 NM_001202438.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88
• Publications: 0 publications found

Genes affected

EDRF1 (HGNC:24640): (erythroid differentiation regulatory factor 1) This gene may play a role in erythroid cell differentiation. The encoded protein inhibits DNA binding of the erythroid transcription factor GATA-1 and may regulate the expression of alpha-globin and gamma-globin. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

EDRF1-AS1 (HGNC:49501): (EDRF1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001202438.2. 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
	EDRF1	NM_001202438.2	MANE Select	c.1247A>G	p.Lys416Arg	missense	Exon 10 of 25	NP_001189367.1	Q3B7T1-1
	EDRF1	NM_015608.3		c.1145A>G	p.Lys382Arg	missense	Exon 9 of 24	NP_056423.2
	EDRF1	NR_110857.2		n.1346A>G		non_coding_transcript_exon	Exon 10 of 25

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDRF1	ENST00000356792.9	TSL:1 MANE Select	c.1247A>G	p.Lys416Arg	missense	Exon 10 of 25	ENSP00000349244.4	Q3B7T1-1
	EDRF1	ENST00000368815.6	TSL:1	n.1247A>G		non_coding_transcript_exon	Exon 10 of 25	ENSP00000357805.2	Q3B7T1-4
	EDRF1	ENST00000419769.6	TSL:1	n.1247A>G		non_coding_transcript_exon	Exon 10 of 26	ENSP00000396544.2	Q3B7T1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448276 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721578

African (AFR) AF: 0.00 AC: 0 AN: 33182

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099902

Other (OTH) AF: 0.00 AC: 0 AN: 59874

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.9
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.27		Loss of methylation at K416 (P = 0.0112)
MVP		0.74
MPC		0.37
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.68
gMVP		0.39
Mutation Taster		=26/74	disease causing

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

Other links and lift over

hg19: chr10-127422091;