13-73943984-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000377669.7(KLF12):c.120A>C(p.Gln40His) variant causes a missense change. The variant allele was found at a frequency of 0.00000963 in 1,454,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: KLF12 ENST00000377669.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34613675).
• BS2: High AC in GnomAdExome at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF12	NM_001400136.1	c.120A>C	p.Gln40His	missense_variant	3/8	ENST00000703967.1
KLF12	NM_001400153.1	c.120A>C	p.Gln40His	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF12	ENST00000703967.1	c.120A>C	p.Gln40His	missense_variant	3/8		NM_001400136.1	P1
KLF12	ENST00000377669.7	c.120A>C	p.Gln40His	missense_variant	3/8	1		P1
KLF12	ENST00000472022.1	n.154A>C		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250494 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1454090 Hom.: 0 Cov.: 28 AF XY: 0.00000967 AC XY: 7 AN XY: 723920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.120A>C (p.Q40H) alteration is located in exon 3 (coding exon 2) of the KLF12 gene. This alteration results from a A to C substitution at nucleotide position 120, causing the glutamine (Q) at amino acid position 40 to be replaced by a histidine (H). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.25
Sift	Benign	0.039	D
Sift4G	Benign	0.12	T
Polyphen		0.64	P
Vest4		0.70
MutPred		0.18		Gain of sheet (P = 0.0827);
MVP		0.52
MPC		0.34
ClinPred		0.11	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.42

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: rs765752275; hg19: chr13-74518121;