rs267607201
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_006563.5(KLF1):c.973G>A(p.Glu325Lys) 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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
KLF1
NM_006563.5 missense
NM_006563.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 7.84
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
Variant 19-12885001-C-T is Pathogenic according to our data. Variant chr19-12885001-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLF1 | NM_006563.5 | c.973G>A | p.Glu325Lys | missense_variant | 3/3 | ENST00000264834.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLF1 | ENST00000264834.6 | c.973G>A | p.Glu325Lys | missense_variant | 3/3 | 1 | NM_006563.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 22, 2020 | PS3, PS2, PS4_moderate, PM1, PM2, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 20, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2021 | This sequence change replaces glutamic acid with lysine at codon 325 of the KLF1 protein (p.Glu325Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with clinical features of congenital dyserythropoietic anemia (PMID: 21055716, 23522491, 28102861, 29200155, 29300242, 29396846). ClinVar contains an entry for this variant (Variation ID: 18447). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects KLF1 function (PMID: 21055716, 21778342). For these reasons, this variant has been classified as Pathogenic. - |
Congenital dyserythropoietic anemia type 4 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.E325K in KLF1 (NM_006563.5) has been previously reported in dominant state with congenital dyseryhtropoietic anemia (Arnaud L et al). Functional studies reveal a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.E325K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E325K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 325 of KLF1 is conserved in all mammalian species. The nucleotide c.973 in KLF1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
BLOOD GROUP--LUTHERAN INHIBITOR Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0146);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at