NM_006563.5:c.*277C>T

Variant names:

• chr19-12884608-G-A
• rs16978757
• NM_006563.5:c.*277C>T

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.*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
• Publications: 6 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 (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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006563.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF1	NM_006563.5	MANE Select	c.*277C>T		3_prime_UTR	Exon 3 of 3	NP_006554.1	Q13351

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF1	ENST00000264834.6	TSL:1 MANE Select	c.*277C>T		3_prime_UTR	Exon 3 of 3	ENSP00000264834.3	Q13351
	KLF1	ENST00000876185.1		c.*277C>T		3_prime_UTR	Exon 3 of 3	ENSP00000546244.1

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

African (AFR) AF: 0.182 AC: 1878 AN: 10314

American (AMR) AF: 0.0121 AC: 183 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10940

East Asian (EAS) AF: 0.0000449 AC: 1 AN: 22264

South Asian (SAS) AF: 0.000397 AC: 17 AN: 42820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19650

Middle Eastern (MID) AF: 0.00714 AC: 11 AN: 1540

European-Non Finnish (NFE) AF: 0.000240 AC: 50 AN: 208530

Other (OTH) AF: 0.0133 AC: 269 AN: 20300

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

African (AFR) AF: 0.178 AC: 7404 AN: 41486

American (AMR) AF: 0.0164 AC: 251 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67998

Other (OTH) AF: 0.0356 AC: 75 AN: 2108

Alfa AF: 0.0214 Hom.: 699

Bravo AF: 0.0580

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital dyserythropoietic anemia type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.75
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs16978757; hg19: chr19-12995422;