13-73846168-G-A

Variant names:

• chr13-73846168-G-A
• rs1311779192
• ENST00000377669.7:c.329C>T

Variant summary

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

The NM_007249.5(KLF12):​c.329C>T​(p.Pro110Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KLF12 NM_007249.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

Genes affected

KLF12 (HGNC:6346): (KLF transcription factor 12) Activator protein-2 alpha (AP-2 alpha) is a developmentally-regulated transcription factor and important regulator of gene expression during vertebrate development and carcinogenesis. The protein encoded by this gene is a member of the Kruppel-like zinc finger protein family and can repress expression of the AP-2 alpha gene by binding to a specific site in the AP-2 alpha gene promoter. Repression by the encoded protein requires binding with a corepressor, CtBP1. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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
KLF12	NM_001400136.1	c.329C>T	p.Pro110Leu	missense_variant	Exon 4 of 8		NP_001387065.1
KLF12	NM_001400139.1	c.329C>T	p.Pro110Leu	missense_variant	Exon 4 of 8		NP_001387068.1
KLF12	NM_001400141.1	c.329C>T	p.Pro110Leu	missense_variant	Exon 4 of 8		NP_001387070.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF12	ENST00000377669.7	c.329C>T	p.Pro110Leu	missense_variant	Exon 4 of 8	1		ENSP00000366897.2
KLF12	ENST00000703967.1	c.329C>T	p.Pro110Leu	missense_variant	Exon 4 of 8			ENSP00000515592.1
KLF12	ENST00000472022.1	n.363C>T		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.329C>T (p.P110L) alteration is located in exon 4 (coding exon 3) of the KLF12 gene. This alteration results from a C to T substitution at nucleotide position 329, causing the proline (P) at amino acid position 110 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.086
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.047	D
Polyphen		0.32	B
Vest4		0.71
MutPred		0.24		Loss of glycosylation at P110 (P = 0.0078);
MVP		0.28
MPC		0.40
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.40

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: rs1311779192; hg19: chr13-74420305;