chr10-3781852-G-C

Variant names:

• chr10-3781852-G-C
• rs121909144
• NM_001300.6:c.465C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PS1 PM2 PP2 BP4_Moderate

The NM_001300.6(KLF6):​c.465C>G​(p.Ser155Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• 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: 2.46
• 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 5 ACMG points.

• PS1: Transcript NM_001300.6 (KLF6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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=0.16149423).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	NM_001300.6	MANE Select	c.465C>G	p.Ser155Arg	missense	Exon 2 of 4	NP_001291.3
	KLF6	NM_001160124.2		c.465C>G	p.Ser155Arg	missense	Exon 2 of 4	NP_001153596.1
	KLF6	NM_001160125.2		c.465C>G	p.Ser155Arg	missense	Exon 2 of 3	NP_001153597.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	ENST00000497571.6	TSL:1 MANE Select	c.465C>G	p.Ser155Arg	missense	Exon 2 of 4	ENSP00000419923.1
	KLF6	ENST00000469435.1	TSL:1	c.465C>G	p.Ser155Arg	missense	Exon 2 of 2	ENSP00000419079.1
	KLF6	ENST00000542957.1	TSL:5	c.465C>G	p.Ser155Arg	missense	Exon 2 of 3	ENSP00000445301.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

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	0.33
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.031
Sift	Benign	0.038	D
Sift4G	Benign	0.32	T
Polyphen		0.11	B
Vest4		0.17
MutPred		0.27		Loss of phosphorylation at S155 (P = 0.0037)
MVP		0.43
MPC		1.1
ClinPred		0.73	D
GERP RS		2.3
Varity_R		0.14
gMVP		0.46
Mutation Taster		=13/87	disease causing

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: rs121909144; hg19: chr10-3824044;