19-12885926-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006563.5(KLF1):c.304T>C(p.Ser102Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,553,064 control chromosomes in the GnomAD database, including 87,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10644 hom., cov: 33)

Exomes 𝑓: 0.32 ( 77294 hom. )

Consequence

KLF1
NM_006563.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.78

Publications

45 publications found

Variant links:

Genes affected

KLF1 (HGNC:6345): (KLF transcription factor 1) This gene encodes a hematopoietic-specific transcription factor that induces high-level expression of adult beta-globin and other erythroid genes. The zinc-finger protein binds to the DNA sequence CCACACCCT found in the beta hemoglobin promoter. Heterozygous loss-of-function mutations in this gene result in the dominant In(Lu) blood phenotype. [provided by RefSeq, Oct 2009]

KLF1 Gene-Disease associations (from GenCC):

congenital dyserythropoietic anemia type 4
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KLF1 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=1.2060891E-5).

BP6

Variant 19-12885926-A-G is Benign according to our data. Variant chr19-12885926-A-G is described in ClinVar as Benign. ClinVar VariationId is 260001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006563.5. 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
	KLF1	NM_006563.5	MANE Select	c.304T>C	p.Ser102Pro	missense	Exon 2 of 3	NP_006554.1	Q13351

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF1	ENST00000264834.6	TSL:1 MANE Select	c.304T>C	p.Ser102Pro	missense	Exon 2 of 3	ENSP00000264834.3	Q13351
	KLF1	ENST00000876185.1		c.421T>C	p.Ser141Pro	missense	Exon 2 of 3	ENSP00000546244.1

Frequencies

GnomAD3 genomes

AF:

0.364

AC:

55404

AN:

152036

Hom.:

10616

Cov.:

show subpopulations

Gnomad AFR

AF:

0.432

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.620

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.372

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.335

GnomAD2 exomes

AF:

0.369

AC:

56176

AN:

152404

AF XY:

0.370

show subpopulations

Gnomad AFR exome

AF:

0.438

Gnomad AMR exome

AF:

0.370

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.620

Gnomad FIN exome

AF:

0.372

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.323

GnomAD4 exome

AF:

0.324

AC:

453203

AN:

1400910

Hom.:

77294

Cov.:

AF XY:

0.326

AC XY:

225463

AN XY:

691372

show subpopulations

African (AFR)

AF:

0.440

AC:

13927

AN:

31670

American (AMR)

AF:

0.364

AC:

13173

AN:

36158

Ashkenazi Jewish (ASJ)

AF:

0.252

AC:

6339

AN:

25114

East Asian (EAS)

AF:

0.673

AC:

24198

AN:

35940

South Asian (SAS)

AF:

0.430

AC:

34275

AN:

79724

European-Finnish (FIN)

AF:

0.366

AC:

17576

AN:

48048

Middle Eastern (MID)

AF:

0.275

AC:

1547

AN:

5626

European-Non Finnish (NFE)

AF:

0.298

AC:

322446

AN:

1080586

Other (OTH)

AF:

0.340

AC:

19722

AN:

58044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

18661

37322

55983

74644

93305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10976

21952

32928

43904

54880

<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:

0.365

AC:

55476

AN:

152154

Hom.:

10644

Cov.:

AF XY:

0.373

AC XY:

27720

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.433

AC:

17984

AN:

41524

American (AMR)

AF:

0.371

AC:

5672

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

912

AN:

3468

East Asian (EAS)

AF:

0.621

AC:

3205

AN:

5162

South Asian (SAS)

AF:

0.460

AC:

2220

AN:

4826

European-Finnish (FIN)

AF:

0.372

AC:

3941

AN:

10594

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.303

AC:

20579

AN:

67962

Other (OTH)

AF:

0.332

AC:

701

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1862

3723

5585

7446

9308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.326

Hom.:

4380

Bravo

AF:

0.360

TwinsUK

AF:

0.300

AC:

1112

ALSPAC

AF:

0.301

AC:

1159

ESP6500AA

AF:

0.337

AC:

1336

ESP6500EA

AF:

0.236

AC:

1826

ExAC

AF:

0.276

AC:

27521

Asia WGS

AF:

0.522

AC:

1810

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Congenital dyserythropoietic anemia type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.12

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.064

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.12

MetaRNN

Benign

0.000012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

-1.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.22

REVEL

Benign

0.0080

Sift

Benign

0.28

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.0090

MPC

0.88

ClinPred

0.0040

GERP RS

-2.9

Varity_R

0.047

gMVP

0.070

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over