rs267607201

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

Scores

8
7
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.84
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]

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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
KLF1NM_006563.5 linkuse as main transcriptc.973G>A p.Glu325Lys missense_variant 3/3 ENST00000264834.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KLF1ENST00000264834.6 linkuse as main transcriptc.973G>A p.Glu325Lys missense_variant 3/31 NM_006563.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 22, 2020PS3, PS2, PS4_moderate, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 20, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeAug 10, 2021This 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 providedliterature onlyOMIMJan 01, 2013- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg 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 submitterclinical testingMendelicsMay 28, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.45
T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.73
T
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
-0.15
N
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Uncertain
-3.8
D
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.92
MutPred
0.92
Gain of MoRF binding (P = 0.0146);
MVP
0.81
MPC
1.8
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.74
gMVP
0.75

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

LitVar

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

Other links and lift over

dbSNP: rs267607201; hg19: chr19-12995815; API