10-3781883-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001300.6(KLF6):​c.434C>A​(p.Thr145Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T145I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLF6 NM_001300.6 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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=0.27114534).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	NM_001300.6	MANE Select	c.434C>A	p.Thr145Asn	missense	Exon 2 of 4	NP_001291.3
	KLF6	NM_001160124.2		c.434C>A	p.Thr145Asn	missense	Exon 2 of 4	NP_001153596.1	D3GC14
	KLF6	NM_001160125.2		c.434C>A	p.Thr145Asn	missense	Exon 2 of 3	NP_001153597.1	Q99612-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	ENST00000497571.6	TSL:1 MANE Select	c.434C>A	p.Thr145Asn	missense	Exon 2 of 4	ENSP00000419923.1	Q99612-1
	KLF6	ENST00000469435.1	TSL:1	c.434C>A	p.Thr145Asn	missense	Exon 2 of 2	ENSP00000419079.1	Q99612-2
	KLF6	ENST00000875520.1		c.434C>A	p.Thr145Asn	missense	Exon 2 of 4	ENSP00000545579.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 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: 0.00 AC: 0 AN: 1112008

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.055
Sift	Benign	0.070	T
Sift4G	Benign	0.50	T
Polyphen		0.96	D
Vest4		0.31
MutPred		0.17		Loss of glycosylation at T145 (P = 0.0034)
MVP		0.56
MPC		1.6
ClinPred		0.65	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.31
Mutation Taster		=90/10	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;