13-73059535-C-A

Variant names:

• chr13-73059535-C-A
• rs2044613919
• NM_001730.5:c.208C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001730.5(KLF5):​c.208C>A​(p.Pro70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000966 in 1,035,330 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P70L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: KLF5 NM_001730.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.693
• Publications: 0 publications found

Genes affected

KLF5 (HGNC:6349): (KLF transcription factor 5) This gene encodes a member of the Kruppel-like factor subfamily of zinc finger proteins. The encoded protein is a transcriptional activator that binds directly to a specific recognition motif in the promoters of target genes. This protein acts downstream of multiple different signaling pathways and is regulated by post-translational modification. It may participate in both promoting and suppressing cell proliferation. Expression of this gene may be changed in a variety of different cancers and in cardiovascular disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066111535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001730.5. 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
	KLF5	NM_001730.5	MANE Select	c.208C>A	p.Pro70Thr	missense	Exon 1 of 4	NP_001721.2
	KLF5	NM_001286818.2		c.-12-2326C>A		intron	N/A	NP_001273747.1	Q13887-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF5	ENST00000377687.6	TSL:1 MANE Select	c.208C>A	p.Pro70Thr	missense	Exon 1 of 4	ENSP00000366915.4	Q13887-1
	KLF5	ENST00000539231.5	TSL:1	c.-12-2326C>A		intron	N/A	ENSP00000440407.1	Q13887-4
	KLF5	ENST00000851191.1		c.208C>A	p.Pro70Thr	missense	Exon 1 of 3	ENSP00000521250.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.66e-7 AC: 1 AN: 1035330 Hom.: 0 Cov.: 30 AF XY: 0.00000203 AC XY: 1 AN XY: 493442

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20766

American (AMR) AF: 0.00 AC: 0 AN: 6600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11564

East Asian (EAS) AF: 0.0000485 AC: 1 AN: 20614

South Asian (SAS) AF: 0.00 AC: 0 AN: 20238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2628

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 895022

Other (OTH) AF: 0.00 AC: 0 AN: 39586

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.6
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.69
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.81	N
REVEL	Benign	0.089
Sift	Benign	0.88	T
Sift4G	Benign	0.25	T
Polyphen		0.028	B
Vest4		0.052
MutPred		0.18		Gain of phosphorylation at P70 (P = 0.0065)
MVP		0.25
MPC		0.25
ClinPred		0.074	T
GERP RS		4.3
Varity_R		0.040
gMVP		0.19
Mutation Taster		=86/14	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: rs2044613919; hg19: chr13-73633673;