NM_006563.5:c.304T>C

Variant names:

• chr19-12885926-A-G
• rs2072597
• NM_006563.5:c.304T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.78
• Publications: 45 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), G2P, Ambry Genetics, Orphanet
• 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: Benign. The variant received -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 VariationId is 260001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
KLF1	NM_006563.5	c.304T>C	p.Ser102Pro	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.304T>C	p.Ser102Pro	missense_variant	Exon 2 of 3	1	NM_006563.5	ENSP00000264834.3

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55404 AN: 152036 Hom.: 10616 Cov.: 33

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

GnomAD2 exomes AF: 0.369 AC: 56176 AN: 152404 AF XY: 0.370

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 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.: 37 AF XY: 0.326 AC XY: 225463 AN XY: 691372

African (AFR) AF: 0.440 AC: 13927 AN: 31670

American (AMR) AF: 0.364 AC: 13173 AN: 36158

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6339 AN: 25114

East Asian (EAS) AF: 0.673 AC: 24198 AN: 35940

South Asian (SAS) AF: 0.430 AC: 34275 AN: 79724

European-Finnish (FIN) AF: 0.366 AC: 17576 AN: 48048

Middle Eastern (MID) AF: 0.275 AC: 1547 AN: 5626

European-Non Finnish (NFE) AF: 0.298 AC: 322446 AN: 1080586

Other (OTH) AF: 0.340 AC: 19722 AN: 58044

GnomAD4 genome AF: 0.365 AC: 55476 AN: 152154 Hom.: 10644 Cov.: 33 AF XY: 0.373 AC XY: 27720 AN XY: 74384

African (AFR) AF: 0.433 AC: 17984 AN: 41524

American (AMR) AF: 0.371 AC: 5672 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3468

East Asian (EAS) AF: 0.621 AC: 3205 AN: 5162

South Asian (SAS) AF: 0.460 AC: 2220 AN: 4826

European-Finnish (FIN) AF: 0.372 AC: 3941 AN: 10594

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20579 AN: 67962

Other (OTH) AF: 0.332 AC: 701 AN: 2110

Alfa AF: 0.326 Hom.: 4380

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

Submissions by phenotype

not provided Benign:3

Dec 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29420372, 29047116, 23125034, 27043150, 24711040) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.47
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-1.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.0080
Sift	Benign	0.28	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.88
ClinPred		0.0040	T
GERP RS		-2.9
Varity_R		0.047
gMVP		0.070
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072597; hg19: chr19-12996740; COSMIC: COSV53434385; COSMIC: COSV53434385;