chr15-89649841-CACATGT-C

Variant names:

• chr15-89649841-CACATGT-C
• rs1555425036
• NM_198525.3:c.423_428delACATGT

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 rank	MANE	Protein	UniProt
KIF7	NM_198525.3	c.423_428delACATGT	p.His142_Val143del	disruptive_inframe_deletion	Exon 3 of 19	ENST00000394412.8	NP_940927.2

Ensembl

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

May 18, 2017

Institute of Medical Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;