rs780942335

Variant names:

• chr15-89628453-GGGCTGGCTCGTC-G
• rs780942335
• NM_198525.3:c.3986_3997delGACGAGCCAGCC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_198525.3(KIF7):​c.3986_3997delGACGAGCCAGCC​(p.Arg1329_Ser1332del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00026 in 1,609,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: KIF7 NM_198525.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.34

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]

TICRR (HGNC:28704): (TOPBP1 interacting checkpoint and replication regulator) Enables chromatin binding activity. Involved in regulation of DNA-dependent DNA replication initiation. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_198525.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3	c.3986_3997delGACGAGCCAGCC	p.Arg1329_Ser1332del	disruptive_inframe_deletion	Exon 19 of 19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.3986_3997delGACGAGCCAGCC	p.Arg1329_Ser1332del	disruptive_inframe_deletion	Exon 19 of 19	5	NM_198525.3	ENSP00000377934.3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 48 AN: 245798 Hom.: 0 AF XY: 0.000239 AC XY: 32 AN XY: 133850

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000268 AC: 390 AN: 1457578 Hom.: 0 AF XY: 0.000246 AC XY: 178 AN XY: 724652

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74336

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000200

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Apr 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Acrocallosal syndrome Uncertain:1

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3986_3997del, results in the deletion of 4 amino acid(s) of the KIF7 protein (p.Arg1329_Ser1332del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs780942335, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with KIF7-related conditions. ClinVar contains an entry for this variant (Variation ID: 30902). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial aplasia of the vermis Uncertain:1

Jul 01, 2011

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs780942335; hg19: chr15-90171684;