rs146429909

Variant names:

• chrX-56265420-A-G
• rs146429909
• NM_007250.5:c.322A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-56265420-A-G
• chrX-56265420-A-T

Variant summary

Our verdict is Benign. The variant received -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. 13/22 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:4
• Conservation: PhyloP100: -0.354
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 211311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 136 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007250.5. 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
	KLF8	NM_007250.5	MANE Select	c.322A>G	p.Ile108Val	missense	Exon 3 of 6	NP_009181.2	O95600-1
	KLF8	NM_001324104.1		c.337A>G	p.Ile113Val	missense	Exon 4 of 7	NP_001311033.1
	KLF8	NM_001324102.1		c.322A>G	p.Ile108Val	missense	Exon 4 of 7	NP_001311031.1	O95600-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF8	ENST00000468660.6	TSL:1 MANE Select	c.322A>G	p.Ile108Val	missense	Exon 3 of 6	ENSP00000417303.1	O95600-1
	KLF8	ENST00000640927.1	TSL:1	c.307A>G	p.Ile103Val	missense	Exon 2 of 4	ENSP00000492126.1	O95600-4
	KLF8	ENST00000358094.7	TSL:1	n.322A>G		non_coding_transcript_exon	Exon 3 of 7	ENSP00000431911.1	Q05BZ3

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 419 AN: 111446 Hom.: 1 Cov.: 22

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

GnomAD2 exomes AF: 0.00444 AC: 811 AN: 182849 AF XY: 0.00461

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 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

African (AFR) AF: 0.000682 AC: 18 AN: 26396

American (AMR) AF: 0.000625 AC: 22 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.000568 AC: 11 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00137 AC: 74 AN: 54119

European-Finnish (FIN) AF: 0.00982 AC: 398 AN: 40520

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4133

European-Non Finnish (NFE) AF: 0.00767 AC: 6454 AN: 841880

Other (OTH) AF: 0.00456 AC: 210 AN: 46090

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

African (AFR) AF: 0.000878 AC: 27 AN: 30749

American (AMR) AF: 0.000857 AC: 9 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.000756 AC: 2 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00191 AC: 5 AN: 2620

European-Finnish (FIN) AF: 0.0103 AC: 62 AN: 5999

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00590 AC: 313 AN: 53019

Other (OTH) AF: 0.000658 AC: 1 AN: 1520

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.066	T
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.26	N
PhyloP100		-0.35
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.0090
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs146429909; hg19: chrX-56291853;