rs2072597

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006563.5(KLF1):c.304T>C(p.Ser102Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,553,064 control chromosomes in the GnomAD database, including 87,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10644 hom., cov: 33)

Exomes 𝑓: 0.32 ( 77294 hom. )

Consequence

KLF1
NM_006563.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.78

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]

KLF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2060891E-5).

BP6

Variant 19-12885926-A-G is Benign according to our data. Variant chr19-12885926-A-G is described in ClinVar as [Benign]. Clinvar id is 260001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12885926-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF1	NM_006563.5 linkuse as main transcript	c.304T>C	p.Ser102Pro	missense_variant	2/3	ENST00000264834.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF1	ENST00000264834.6 linkuse as main transcript	c.304T>C	p.Ser102Pro	missense_variant	2/3	1	NM_006563.5	P1

Frequencies

GnomAD3 genomes

AF:

0.364

AC:

55404

AN:

152036

Hom.:

10616

Cov.:

show subpopulations

Gnomad AFR

AF:

0.432

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.620

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.372

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.335

GnomAD3 exomes

AF:

0.369

AC:

56176

AN:

152404

Hom.:

11070

AF XY:

0.370

AC XY:

30458

AN XY:

82422

show subpopulations

Gnomad AFR exome

AF:

0.438

Gnomad AMR exome

AF:

0.370

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.620

Gnomad SAS exome

AF:

0.438

Gnomad FIN exome

AF:

0.372

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.323

GnomAD4 exome

AF:

0.324

AC:

453203

AN:

1400910

Hom.:

77294

Cov.:

AF XY:

0.326

AC XY:

225463

AN XY:

691372

show subpopulations

Gnomad4 AFR exome

AF:

0.440

Gnomad4 AMR exome

AF:

0.364

Gnomad4 ASJ exome

AF:

0.252

Gnomad4 EAS exome

AF:

0.673

Gnomad4 SAS exome

AF:

0.430

Gnomad4 FIN exome

AF:

0.366

Gnomad4 NFE exome

AF:

0.298

Gnomad4 OTH exome

AF:

0.340

GnomAD4 genome

AF:

0.365

AC:

55476

AN:

152154

Hom.:

10644

Cov.:

AF XY:

0.373

AC XY:

27720

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.433

Gnomad4 AMR

AF:

0.371

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.621

Gnomad4 SAS

AF:

0.460

Gnomad4 FIN

AF:

0.372

Gnomad4 NFE

AF:

0.303

Gnomad4 OTH

AF:

0.332

Alfa

AF:

0.314

Hom.:

2754

Bravo

AF:

0.360

TwinsUK

AF:

0.300

AC:

1112

ALSPAC

AF:

0.301

AC:

1159

ESP6500AA

AF:

0.337

AC:

1336

ESP6500EA

AF:

0.236

AC:

1826

ExAC

AF:

0.276

AC:

27521

Asia WGS

AF:

0.522

AC:

1810

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2019	This variant is associated with the following publications: (PMID: 29420372, 29047116, 23125034, 27043150, 24711040) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 44% of total chromosomes in ExAC -

Congenital dyserythropoietic anemia type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.12

DANN

Benign

0.47

DEOGEN2

Benign

0.064

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.12

MetaRNN

Benign

0.000012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.22

REVEL

Benign

0.0080

Sift

Benign

0.28

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.0090

MPC

0.88

ClinPred

0.0040

GERP RS

-2.9

Varity_R

0.047

gMVP

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over