10-3784992-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001300.6(KLF6):c.23G>C(p.Ser8Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,498 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLF6 NM_001300.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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 Uncertain_significance. Variant got 4 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF6	NM_001300.6	c.23G>C	p.Ser8Thr	missense_variant	1/4	ENST00000497571.6
KLF6	NM_001160124.2	c.23G>C	p.Ser8Thr	missense_variant	1/4
KLF6	NM_001160125.2	c.23G>C	p.Ser8Thr	missense_variant	1/3
KLF6	NR_027653.2	n.218G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF6	ENST00000497571.6	c.23G>C	p.Ser8Thr	missense_variant	1/4	1	NM_001300.6	P1
KLF6	ENST00000469435.1	c.23G>C	p.Ser8Thr	missense_variant	1/2	1
KLF6	ENST00000542957.1	c.23G>C	p.Ser8Thr	missense_variant	1/3	5
KLF6	ENST00000380946.3	n.192G>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456498 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.23G>C (p.S8T) alteration is located in exon 1 (coding exon 1) of the KLF6 gene. This alteration results from a G to C substitution at nucleotide position 23, causing the serine (S) at amino acid position 8 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	2.9	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.53
MutPred		0.40		Gain of glycosylation at S8 (P = 0.0856);Gain of glycosylation at S8 (P = 0.0856);Gain of glycosylation at S8 (P = 0.0856);
MVP		0.72
MPC		1.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.69
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-3827184;