rs1555425036

Positions:

• chr15-89649841-CACATGT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_198525.3(KIF7):​c.423_428delACATGT​(p.His142_Val143del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KIF7 NM_198525.3 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.44

Genes affected

KIF7 (HGNC:30497): (kinesin family member 7) This gene encodes a cilia-associated protein belonging to the kinesin family. This protein plays a role in the sonic hedgehog (SHH) signaling pathway through the regulation of GLI transcription factors. It functions as a negative regulator of the SHH pathway by preventing inappropriate activation of GLI2 in the absence of ligand, and as a positive regulator by preventing the processing of GLI3 into its repressor form. Mutations in this gene have been associated with various ciliopathies. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_198525.3.
• PP5: Variant 15-89649841-CACATGT-C is Pathogenic according to our data. Variant chr15-89649841-CACATGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427637.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.423_428delACATGT	p.His142_Val143del	disruptive_inframe_deletion	3/19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.423_428delACATGT	p.His142_Val143del	disruptive_inframe_deletion	3/19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000445906.1	n.*82_*87delACATGT		non_coding_transcript_exon_variant	3/5	1		ENSP00000395906.1
KIF7	ENST00000445906.1	n.*82_*87delACATGT		3_prime_UTR_variant	3/5	1		ENSP00000395906.1
KIF7	ENST00000696512.1	c.546_551delACATGT	p.His183_Val184del	disruptive_inframe_deletion	3/19			ENSP00000512678.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399436 Hom.: 0 AF XY: 0.00000145 AC XY: 1 AN XY: 690228

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acrocallosal syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics, University of Zurich

May 18, 2017

This likely pathogenic variant is believed to be in compound heterozygosity with another pathogenic variant that has yet to be identified. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555425036; hg19: chr15-90193072;