chr10-3781883-G-A

Variant names:

• chr10-3781883-G-A
• rs777889308
• NM_001300.6:c.434C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PM1 PM2 PP2 BP4_Moderate BS2

The NM_001300.6(KLF6):​c.434C>T​(p.Thr145Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KLF6 NM_001300.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29
• Publications: 0 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 -1 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 NM_001300.6
• PM2: Very rare variant in population databases, with high coverage
• 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: 2.6969 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.08044982).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF6	NM_001300.6	c.434C>T	p.Thr145Ile	missense_variant	Exon 2 of 4	ENST00000497571.6	NP_001291.3
KLF6	NM_001160124.2	c.434C>T	p.Thr145Ile	missense_variant	Exon 2 of 4		NP_001153596.1
KLF6	NM_001160125.2	c.434C>T	p.Thr145Ile	missense_variant	Exon 2 of 3		NP_001153597.1
KLF6	NR_027653.2	n.629C>T		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.434C>T	p.Thr145Ile	missense_variant	Exon 2 of 4	1	NM_001300.6	ENSP00000419923.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251258 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.434C>T (p.T145I) alteration is located in exon 2 (coding exon 2) of the KLF6 gene. This alteration results from a C to T substitution at nucleotide position 434, causing the threonine (T) at amino acid position 145 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.020	N;N;N
PhyloP100		5.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.15
MutPred		0.27		Loss of glycosylation at T145 (P = 0.0034);Loss of glycosylation at T145 (P = 0.0034);Loss of glycosylation at T145 (P = 0.0034);
MVP		0.26
MPC		0.90
ClinPred		0.045	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.28
Mutation Taster		=91/9	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: rs777889308; hg19: chr10-3824075;