rs146429909

Positions:

• chrX-56265420-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_007250.5(KLF8):​c.322A>G​(p.Ile108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,209,391 control chromosomes in the GnomAD database, including 18 homozygotes. There are 2,499 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., 136 hem., cov: 22)
  • Exomes 𝑓: 0.0065 (17 hom. 2363 hem.)
• Consequence: KLF8 NM_007250.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.354

Genes affected

KLF8 (HGNC:6351): (KLF transcription factor 8) This gene encodes a protein which is a member of the Sp/KLF family of transcription factors. Members of this family contain a C-terminal DNA-binding domain with three Kruppel-like zinc fingers. The encoded protein is thought to play an important role in the regulation of epithelial to mesenchymal transition, a process which occurs normally during development but also during metastasis. A pseudogene has been identified on chromosome 16. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant X-56265420-A-G is Benign according to our data. Variant chrX-56265420-A-G is described in ClinVar as [Benign]. Clinvar id is 211311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-56265420-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 136 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF8	NM_007250.5	c.322A>G	p.Ile108Val	missense_variant	3/6	ENST00000468660.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF8	ENST00000468660.6	c.322A>G	p.Ile108Val	missense_variant	3/6	1	NM_007250.5	P1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 419 AN: 111446 Hom.: 1 Cov.: 22 AF XY: 0.00404 AC XY: 136 AN XY: 33654

Gnomad AFR AF: 0.000880

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000859

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00190

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.00444 AC: 811 AN: 182849 Hom.: 1 AF XY: 0.00461 AC XY: 311 AN XY: 67431

Gnomad AFR exome AF: 0.000988

Gnomad AMR exome AF: 0.000731

Gnomad ASJ exome AF: 0.000671

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00655 AC: 7189 AN: 1097891 Hom.: 17 Cov.: 31 AF XY: 0.00650 AC XY: 2363 AN XY: 363275

Gnomad4 AFR exome AF: 0.000682

Gnomad4 AMR exome AF: 0.000625

Gnomad4 ASJ exome AF: 0.000568

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00982

Gnomad4 NFE exome AF: 0.00767

Gnomad4 OTH exome AF: 0.00456

GnomAD4 genome AF: 0.00376 AC: 419 AN: 111500 Hom.: 1 Cov.: 22 AF XY: 0.00403 AC XY: 136 AN XY: 33718

Gnomad4 AFR AF: 0.000878

Gnomad4 AMR AF: 0.000857

Gnomad4 ASJ AF: 0.000756

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00191

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00590

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.00471 Hom.: 35

Bravo AF: 0.00290

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00580 AC: 39

ExAC AF: 0.00461 AC: 560

EpiCase AF: 0.00633

EpiControl AF: 0.00612

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 20, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.068
DANN	Benign	0.21
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.62	T;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.26	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.34	N;N;.
REVEL	Benign	0.0090
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.032
MVP		0.44
MPC		0.078
ClinPred		0.00014	T
GERP RS		-0.93
Varity_R		0.033
gMVP		0.082

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146429909; hg19: chrX-56291853;