Genetic Variant NM_006563.5:c.304T>G (chr19-12885926-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006563.5(KLF1):c.304T>G(p.Ser102Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. S102P) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

KLF1
NM_006563.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.78

Publications

0 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), G2P, Ambry Genetics, Orphanet
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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044499755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF1	NM_006563.5 link	c.304T>G	p.Ser102Ala	missense_variant	Exon 2 of 3	ENST00000264834.6	NP_006554.1	Q13351

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF1	ENST00000264834.6 link	c.304T>G	p.Ser102Ala	missense_variant	Exon 2 of 3	1	NM_006563.5	ENSP00000264834.3		Q13351

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1401096

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31686

American (AMR)

AF:

0.00

AC:

AN:

36166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25116

East Asian (EAS)

AF:

0.00

AC:

AN:

35946

South Asian (SAS)

AF:

0.00

AC:

AN:

79742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1080678

Other (OTH)

AF:

0.00

AC:

AN:

58058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.26

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.11

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.15

M_CAP

Benign

0.017

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.55

PhyloP100

-1.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.72

REVEL

Benign

0.0040

Sift

Benign

0.57

Sift4G

Benign

0.58

Polyphen

0.0030

Vest4

0.054

MutPred

0.20

Loss of glycosylation at S102 (P = 1e-04);

MVP

0.22

MPC

0.58

ClinPred

0.030

GERP RS

-2.9

Varity_R

0.036

gMVP

0.066

Mutation Taster

=100/0

polymorphism

(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

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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