10-3781580-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The ENST00000469435.1(KLF6):c.737C>T(p.Ala246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000892 in 1,599,390 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (14 hom.)
• Consequence: KLF6 ENST00000469435.1 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.96

Genes affected

KLF6 (HGNC:2235): (KLF transcription factor 6) This gene encodes a member of the Kruppel-like family of transcription factors. The zinc finger protein is a transcriptional activator, and functions as a tumor suppressor. Multiple transcript variants encoding different isoforms have been found for this gene, some of which are implicated in carcinogenesis. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a chain Krueppel-like factor 6 (size 282) in uniprot entity KLF6_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in ENST00000469435.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.004200399).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00491 (748/152356) while in subpopulation AFR AF= 0.0171 (711/41594). AF 95% confidence interval is 0.0161. There are 4 homozygotes in gnomad4. There are 366 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 747 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF6	NM_001300.6	c.676+61C>T		intron_variant		ENST00000497571.6
KLF6	NM_001160124.2	c.550+187C>T		intron_variant
KLF6	NM_001160125.2	c.676+61C>T		intron_variant
KLF6	NR_027653.2	n.717+215C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF6	ENST00000469435.1	c.737C>T	p.Ala246Val	missense_variant	2/2	1
KLF6	ENST00000497571.6	c.676+61C>T		intron_variant		1	NM_001300.6	P1
KLF6	ENST00000542957.1	c.676+61C>T		intron_variant		5
KLF6	ENST00000173785.4	n.257+215C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00491 AC: 747 AN: 152238 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00106 AC: 230 AN: 216630 Hom.: 3 AF XY: 0.000827 AC XY: 98 AN XY: 118450

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000321

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.000469 AC: 679 AN: 1447034 Hom.: 14 Cov.: 32 AF XY: 0.000383 AC XY: 275 AN XY: 718872

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.000644

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00491 AC: 748 AN: 152356 Hom.: 4 Cov.: 33 AF XY: 0.00491 AC XY: 366 AN XY: 74508

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00526

ExAC AF: 0.00143 AC: 171

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	11
Dann	Uncertain	1.0
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.042
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.12
MVP		0.44
ClinPred		0.015	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs186624120; hg19: chr10-3823772;