19-12884608-G-A

Position:

• chr19-12884608-G-A

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.*277C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 503,670 control chromosomes in the GnomAD database, including 877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (690 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (187 hom.)
• Consequence: KLF1 NM_006563.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.685

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 (BayesDel_noAF=-0.83).
• BP6: Variant 19-12884608-G-A is Benign according to our data. Variant chr19-12884608-G-A is described in ClinVar as [Benign]. Clinvar id is 328308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLF1	NM_006563.5	c.*277C>T		3_prime_UTR_variant	3/3	ENST00000264834.6	NP_006554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLF1	ENST00000264834.6	c.*277C>T		3_prime_UTR_variant	3/3	1	NM_006563.5	ENSP00000264834	P1

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 7758 AN: 152028 Hom.: 691 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0360

GnomAD4 exome AF: 0.00685 AC: 2409 AN: 351524 Hom.: 187 Cov.: 0 AF XY: 0.00571 AC XY: 1062 AN XY: 186022

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000449

Gnomad4 SAS exome AF: 0.000397

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0510 AC: 7757 AN: 152146 Hom.: 690 Cov.: 32 AF XY: 0.0494 AC XY: 3671 AN XY: 74380

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0356

Alfa AF: 0.00787 Hom.: 156

Bravo AF: 0.0580

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital dyserythropoietic anemia type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs16978757; hg19: chr19-12995422;