10-3781892-G-T

Variant names:

• chr10-3781892-G-T
• rs11252089
• NM_001300.6:c.425C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001300.6(KLF6):​c.425C>A​(p.Ser142Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLF6 NM_001300.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF6	NM_001300.6	c.425C>A	p.Ser142Tyr	missense_variant	Exon 2 of 4	ENST00000497571.6	NP_001291.3
KLF6	NM_001160124.2	c.425C>A	p.Ser142Tyr	missense_variant	Exon 2 of 4		NP_001153596.1
KLF6	NM_001160125.2	c.425C>A	p.Ser142Tyr	missense_variant	Exon 2 of 3		NP_001153597.1
KLF6	NR_027653.2	n.620C>A		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF6	ENST00000497571.6	c.425C>A	p.Ser142Tyr	missense_variant	Exon 2 of 4	1	NM_001300.6	ENSP00000419923.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.425C>A (p.S142Y) alteration is located in exon 2 (coding exon 2) of the KLF6 gene. This alteration results from a C to A substitution at nucleotide position 425, causing the serine (S) at amino acid position 142 to be replaced by a tyrosine (Y). 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	Benign	-0.0055	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.99	D;.;P
Vest4		0.49
MutPred		0.36		Gain of catalytic residue at S142 (P = 0.0054);Gain of catalytic residue at S142 (P = 0.0054);Gain of catalytic residue at S142 (P = 0.0054);
MVP		0.60
MPC		1.8
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.38

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: rs11252089; hg19: chr10-3824084; COSMIC: COSV51494773; COSMIC: COSV51494773;