rs397514445

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_StrongBS2_Supporting

The NM_006563.5(KLF1):​c.954dupG​(p.Arg319GlufsTer34) variant causes a frameshift change. The variant allele was found at a frequency of 0.000106 in 1,608,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,Affects (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KLF1
NM_006563.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity; Affects no assertion criteria provided P:2B:1O:1

Conservation

PhyloP100: 6.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.124 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BS2
High AC in GnomAd4 at 9 AD,BG gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLF1NM_006563.5 linkc.954dupG p.Arg319GlufsTer34 frameshift_variant Exon 3 of 3 ENST00000264834.6 NP_006554.1 Q13351

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLF1ENST00000264834.6 linkc.954dupG p.Arg319GlufsTer34 frameshift_variant Exon 3 of 3 1 NM_006563.5 ENSP00000264834.3 Q13351

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152012
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000244
AC:
6
AN:
245656
Hom.:
0
AF XY:
0.0000299
AC XY:
4
AN XY:
133574
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000532
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000111
AC:
161
AN:
1456684
Hom.:
0
Cov.:
31
AF XY:
0.000112
AC XY:
81
AN XY:
724920
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000142
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152012
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
AN XY:
74242
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity; Affects
Submissions summary: Pathogenic:2Benign:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Anemia, congenital dyserythropoietic, type IVb Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2008- -
BLOOD GROUP--LUTHERAN INHIBITOR Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2008- -
KLF1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 14, 2024This 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). -
FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 6 Other:1
Affects, no assertion criteria providedliterature onlyOMIMSep 01, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514445; hg19: chr19-12995833; API