10-3781580-G-A

Variant names:

• chr10-3781580-G-A
• rs186624120
• ENST00000469435.1:c.737C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 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. 12/15 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

Our verdict: Likely_benign. The variant received -6 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.8535 (below the threshold of 3.09). Trascript score misZ: 1.628 (below the threshold of 3.09).
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 748 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF6	NM_001300.6	c.676+61C>T		intron_variant	Intron 2 of 3	ENST00000497571.6	NP_001291.3
KLF6	NM_001160124.2	c.550+187C>T		intron_variant	Intron 2 of 3		NP_001153596.1
KLF6	NM_001160125.2	c.676+61C>T		intron_variant	Intron 2 of 2		NP_001153597.1
KLF6	NR_027653.2	n.717+215C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF6	ENST00000497571.6	c.676+61C>T		intron_variant	Intron 2 of 3	1	NM_001300.6	ENSP00000419923.1

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

GnomAD2 exomes AF: 0.00106 AC: 230 AN: 216630 AF XY: 0.000827

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 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 AC: 561 AN: 33068

Gnomad4 AMR exome AF: 0.000644 AC: 27 AN: 41922

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25838

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38684

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 84786

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52192

Gnomad4 NFE exome AF: 0.0000145 AC: 16 AN: 1104954

Gnomad4 Remaining exome AF: 0.00122 AC: 73 AN: 59840

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 AC: 0.0170938 AN: 0.0170938

Gnomad4 AMR AF: 0.00189 AC: 0.00189394 AN: 0.00189394

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000587976 AN: 0.0000587976

Gnomad4 OTH AF: 0.00189 AC: 0.00189394 AN: 0.00189394

Alfa AF: 0.00275 Hom.: 1

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

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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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
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
Mutation Taster		=98/2	polymorphism

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;