chr19-12884915-G-T

Variant names:

• chr19-12884915-G-T
• NM_006563.5:c.1059C>A
• KLF1 p.His353Gln

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006563.5(KLF1):​c.1059C>A​(p.His353Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H353Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLF1 NM_006563.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

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.1059C>A	p.His353Gln	missense	Exon 3 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.1059C>A	p.His353Gln	missense	Exon 3 of 3	ENSP00000264834.3	Q13351
	KLF1	ENST00000876185.1		c.1176C>A	p.His392Gln	missense	Exon 3 of 3	ENSP00000546244.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.94	L
PhyloP100		2.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.89
gMVP		0.60
Mutation Taster		=79/21	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-12995729;