19-12885356-T-C

Variant names:

• chr19-12885356-T-C
• rs137852687
• NM_006563.5:c.874A>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_006563.5(KLF1):​c.874A>G​(p.Lys292Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,450,660 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KLF1 NM_006563.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 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
KLF1	NM_006563.5	c.874A>G	p.Lys292Glu	missense_variant	Exon 2 of 3	ENST00000264834.6	NP_006554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF1	ENST00000264834.6	c.874A>G	p.Lys292Glu	missense_variant	Exon 2 of 3	1	NM_006563.5	ENSP00000264834.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1450660 Hom.: 0 Cov.: 30 AF XY: 0.00000416 AC XY: 3 AN XY: 720848

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: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.74		Loss of MoRF binding (P = 0.003);
MVP		0.92
MPC		2.0
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.76
gMVP		0.58

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

Other links and lift over

dbSNP: rs137852687; hg19: chr19-12996170;