rs2072597

chr19-12885926-A-Gchr19-12885926-A-T

Variant summary

Our verdict is Benign. Variant got -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. 12/19 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:5
• Conservation: PhyloP100: -1.78

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 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	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	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.: 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

GnomAD3 exomes AF: 0.369 AC: 56176 AN: 152404 Hom.: 11070 AF XY: 0.370 AC XY: 30458 AN XY: 82422

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

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.: 33 AF XY: 0.373 AC XY: 27720 AN XY: 74384

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

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	Invitae	Jan 31, 2024	- -

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	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
MutationTaster	Benign	1.0	P
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

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