rs35476458

Positions:

• chr2-10048470-C-G
• chr2-10048470-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_003597.5(KLF11):​c.1133C>G​(p.Ser378Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,750 control chromosomes in the GnomAD database, including 1 homozygotes. 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. S378F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (1 hom.)
• Consequence: KLF11 NM_003597.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13

Genes affected

KLF11 (HGNC:11811): (KLF transcription factor 11) The protein encoded by this gene is a zinc finger transcription factor that binds to SP1-like sequences in epsilon- and gamma-globin gene promoters. This binding inhibits cell growth and causes apoptosis. Defects in this gene are a cause of maturity-onset diabetes of the young type 7 (MODY7). Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLF11	NM_003597.5	c.1133C>G	p.Ser378Cys	missense_variant	3/4	ENST00000305883.6	NP_003588.1
KLF11	NM_001177716.2	c.1082C>G	p.Ser361Cys	missense_variant	3/4		NP_001171187.1
KLF11	NM_001177718.2	c.1082C>G	p.Ser361Cys	missense_variant	3/4		NP_001171189.1
KLF11	XM_047446025.1	c.1082C>G	p.Ser361Cys	missense_variant	3/4		XP_047301981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLF11	ENST00000305883.6	c.1133C>G	p.Ser378Cys	missense_variant	3/4	1	NM_003597.5	ENSP00000307023.1
KLF11	ENST00000535335.1	c.1082C>G	p.Ser361Cys	missense_variant	3/4	2		ENSP00000442722.1
KLF11	ENST00000540845.5	c.1082C>G	p.Ser361Cys	missense_variant	3/4	2		ENSP00000444690.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461750 Hom.: 1 Cov.: 37 AF XY: 0.00000413 AC XY: 3 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	T;T;.
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.43
MutPred		0.40		Loss of disorder (P = 0.1142);.;.;
MVP		0.79
MPC		0.16
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.47

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: rs35476458; hg19: chr2-10188597;