chr2-207167139-C-A

Position:

• chr2-207167139-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000421199.5(KLF7):​c.3+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLF7 ENST00000421199.5 splice_donor, intron
• Scores: Splicing: ADA: 0.0002919
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.449

Genes affected

KLF7 (HGNC:6350): (KLF transcription factor 7) The protein encoded by this gene is a member of the Kruppel-like transcriptional regulator family. Members in this family regulate cell proliferation, differentiation and survival and contain three C2H2 zinc fingers at the C-terminus that mediate binding to GC-rich sites. This protein may contribute to the progression of type 2 diabetes by inhibiting insulin expression and secretion in pancreatic beta-cells and by deregulating adipocytokine secretion in adipocytes. A pseudogene of this gene is located on the long arm of chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

MYOSLID (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLF7	XM_047446145.1	c.-284G>T		5_prime_UTR_premature_start_codon_gain_variant	1/5		XP_047302101.1
KLF7	XM_047446147.1	c.-361G>T		5_prime_UTR_premature_start_codon_gain_variant	1/6		XP_047302103.1
KLF7	XM_047446145.1	c.-284G>T		5_prime_UTR_variant	1/5		XP_047302101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLF7	ENST00000421199.5	c.3+1G>T		splice_donor_variant, intron_variant		1		ENSP00000387510.1
KLF7	ENST00000457962.5	c.-284G>T		5_prime_UTR_premature_start_codon_gain_variant	1/3	4		ENSP00000392015.1
KLF7	ENST00000457962.5	c.-284G>T		5_prime_UTR_variant	1/3	4		ENSP00000392015.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1288916 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 636130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 29, 2020

The heterozygous c.3+1G>T splice site variant identified in KLF7 has not been reported in the literature in affected individuals and is absent from the gnomAD database indicating it is an extremely rare allele in the general population. The variant affects the canonical splice donor site in intron1of the KLF7 gene and is predicted to cause abnormal gene splicing, either subjecting the transcript to nonsense-mediated mRNA decay orresulting inan abnormal protein product if the message is used for protein translation. The KLF7gene has at least 4 different protein-coding isoforms each with a unique transcriptional and translational start site [https://www.ncbi.nlm.nih.gov/gene/8609]. The c.3+1G>Tsplice site variant is located in intron 1 of the isoform NM_001270943.1 and would not affect normal splicing of the remaining three isoforms. Therefore, potential consequences of c.3+1G>T variant on normal function(s) of KLF7 are unclear at this time. Based on the current evidence, the c.3+1G>T splice site variant in the KLF7 gene is assessed as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.71
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.023	N
MutationTaster	Benign	1.0	N
GERP RS		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.0040

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

Publications

LitVar

Other links and lift over

dbSNP: rs2078739906; hg19: chr2-208031863;