3-126352009-A-G

Position:

• chr3-126352009-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014079.4(KLF15):​c.914T>C​(p.Met305Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000213 in 1,409,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000021 (0 hom.)
• Consequence: KLF15 NM_014079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23

Genes affected

KLF15 (HGNC:14536): (KLF transcription factor 15) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of peptidyl-lysine acetylation and positive regulation of transcription by RNA polymerase II. Located in nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12664059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF15	NM_014079.4	c.914T>C	p.Met305Thr	missense_variant	2/3	ENST00000296233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF15	ENST00000296233.4	c.914T>C	p.Met305Thr	missense_variant	2/3	1	NM_014079.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1409718 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 696138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000342

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Mar 29, 2022

The c.914T>C (p.M305T) alteration is located in exon 2 (coding exon 1) of the KLF15 gene. This alteration results from a T to C substitution at nucleotide position 914, causing the methionine (M) at amino acid position 305 to be replaced by a threonine (T). 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	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.72	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.060
Sift	Benign	0.29	T
Sift4G	Benign	0.74	T
Polyphen		0.012	B
Vest4		0.22
MutPred		0.57		Loss of glycosylation at K308 (P = 0.0236);
MVP		0.30
MPC		0.18
ClinPred		0.17	T
GERP RS		5.3
Varity_R		0.17
gMVP		0.36

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: rs1338386027; hg19: chr3-126070852;