rs4444493

Positions:

• chr2-10053051-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003597.5(KLF11):​c.*544C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 392,436 control chromosomes in the GnomAD database, including 2,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (680 hom., cov: 33)
  • Exomes 𝑓: 0.10 (1450 hom.)
• Consequence: KLF11 NM_003597.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.558

Genes affected

KLF11 (HGNC:11811): (KLF transcription factor 11) The protein encoded by this gene is a zinc finger transcription factor that binds to SP1-like sequences in epsilon- and gamma-globin gene promoters. This binding inhibits cell growth and causes apoptosis. Defects in this gene are a cause of maturity-onset diabetes of the young type 7 (MODY7). Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-10053051-C-A is Benign according to our data. Variant chr2-10053051-C-A is described in ClinVar as [Benign]. Clinvar id is 330654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLF11	NM_003597.5	c.*544C>A		3_prime_UTR_variant	4/4	ENST00000305883.6	NP_003588.1
KLF11	NM_001177716.2	c.*544C>A		3_prime_UTR_variant	4/4		NP_001171187.1
KLF11	NM_001177718.2	c.*544C>A		3_prime_UTR_variant	4/4		NP_001171189.1
KLF11	XM_047446025.1	c.*544C>A		3_prime_UTR_variant	4/4		XP_047301981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLF11	ENST00000305883.6	c.*544C>A		3_prime_UTR_variant	4/4	1	NM_003597.5	ENSP00000307023	A2
KLF11	ENST00000535335.1	c.*544C>A		3_prime_UTR_variant	4/4	2		ENSP00000442722	P4
KLF11	ENST00000540845.5	c.*544C>A		3_prime_UTR_variant	4/4	2		ENSP00000444690	P4

Frequencies

GnomAD3 genomes AF: 0.0838 AC: 12748 AN: 152120 Hom.: 680 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.0876

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0628

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0986

GnomAD4 exome AF: 0.100 AC: 24105 AN: 240198 Hom.: 1450 Cov.: 0 AF XY: 0.101 AC XY: 12357 AN XY: 121834

Gnomad4 AFR exome AF: 0.0346

Gnomad4 AMR exome AF: 0.0789

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0709

Gnomad4 FIN exome AF: 0.0770

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.0973

GnomAD4 genome AF: 0.0837 AC: 12749 AN: 152238 Hom.: 680 Cov.: 33 AF XY: 0.0808 AC XY: 6016 AN XY: 74416

Gnomad4 AFR AF: 0.0330

Gnomad4 AMR AF: 0.0875

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0624

Gnomad4 FIN AF: 0.0688

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.0980

Alfa AF: 0.117 Hom.: 1175

Bravo AF: 0.0842

Asia WGS AF: 0.0330 AC: 116 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Maturity-onset diabetes of the young type 7 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	-0.81
CADD	Benign	2.3
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs4444493; hg19: chr2-10193178;