ENST00000469435.1:c.704C>T

Variant names:

• chr10-3781613-G-A
• rs192712828
• ENST00000469435.1:c.704C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 3P and 8B. PM1 PP2 BP4_Strong BS2

The ENST00000469435.1(KLF6):​c.704C>T​(p.Ala235Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,609,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: KLF6 ENST00000469435.1 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.0460
• Publications: 1 publications found

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 -5 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 1 benign (83%) 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=0.00426051).
• BS2: High AC in GnomAd4 at 288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF6	NM_001300.6	c.676+28C>T		intron_variant	Intron 2 of 3	ENST00000497571.6	NP_001291.3
KLF6	NM_001160124.2	c.550+154C>T		intron_variant	Intron 2 of 3		NP_001153596.1
KLF6	NM_001160125.2	c.676+28C>T		intron_variant	Intron 2 of 2		NP_001153597.1
KLF6	NR_027653.2	n.717+182C>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+28C>T		intron_variant	Intron 2 of 3	1	NM_001300.6	ENSP00000419923.1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000521 AC: 122 AN: 234248 AF XY: 0.000466

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.000239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000876

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000227 AC: 331 AN: 1456828 Hom.: 2 Cov.: 32 AF XY: 0.000221 AC XY: 160 AN XY: 724446

African (AFR) AF: 0.00608 AC: 203 AN: 33374

American (AMR) AF: 0.000250 AC: 11 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000883 AC: 98 AN: 1109786

Other (OTH) AF: 0.000216 AC: 13 AN: 60086

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.00179 AC XY: 133 AN XY: 74488

African (AFR) AF: 0.00650 AC: 270 AN: 41568

American (AMR) AF: 0.000653 AC: 10 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.00202

ESP6500AA AF: 0.00554 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000630 AC: 76

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	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.2
DANN	Uncertain	1.0
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.046
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.028
Sift	Benign	0.077	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.16	B
Vest4		0.19
MVP		0.60
ClinPred		0.014	T
GERP RS		-1.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs192712828; hg19: chr10-3823805; COSMIC: COSV99434870; COSMIC: COSV99434870;