10-3781824-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1 BP4_Strong BP6_Moderate BS1 BS2

The NM_001300.6(KLF6):c.493G>A(p.Val165Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,614,200 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (52 hom.)
• Consequence: KLF6 NM_001300.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.652

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 -12 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 NM_001300.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018826723).
• BP6: Variant 10-3781824-C-T is Benign according to our data. Variant chr10-3781824-C-T is described in ClinVar as [Benign]. Clinvar id is 134634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0147 (2235/152320) while in subpopulation AFR AF= 0.0504 (2093/41562). AF 95% confidence interval is 0.0486. There are 62 homozygotes in gnomad4. There are 1011 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF6	NM_001300.6	c.493G>A	p.Val165Met	missense_variant	2/4	ENST00000497571.6
KLF6	NM_001160124.2	c.493G>A	p.Val165Met	missense_variant	2/4
KLF6	NM_001160125.2	c.493G>A	p.Val165Met	missense_variant	2/3
KLF6	NR_027653.2	n.688G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF6	ENST00000497571.6	c.493G>A	p.Val165Met	missense_variant	2/4	1	NM_001300.6	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2225 AN: 152202 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00411 AC: 1033 AN: 251398 Hom.: 18 AF XY: 0.00309 AC XY: 420 AN XY: 135892

Gnomad AFR exome AF: 0.0523

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000815

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00160 AC: 2335 AN: 1461880 Hom.: 52 Cov.: 32 AF XY: 0.00140 AC XY: 1021 AN XY: 727234

Gnomad4 AFR exome AF: 0.0513

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.0147 AC: 2235 AN: 152320 Hom.: 62 Cov.: 33 AF XY: 0.0136 AC XY: 1011 AN XY: 74500

Gnomad4 AFR AF: 0.0504

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00260 Hom.: 8

Bravo AF: 0.0159

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0540 AC: 238

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00483 AC: 586

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 17, 2018

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	10
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.84	N;N;N
REVEL	Benign	0.017
Sift	Uncertain	0.026	D;D;D
Sift4G	Benign	0.10	T;T;D
Polyphen		0.046	B;.;B
Vest4		0.068
MVP		0.28
MPC		0.85
ClinPred		0.0025	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.23

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: rs61731927; hg19: chr10-3824016; COSMIC: COSV51495858; COSMIC: COSV51495858;