rs769890385

Variant names:

• chr15-89632975-ACTT-A
• rs769890385
• NM_198525.3:c.2737_2739delAAG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_198525.3(KIF7):​c.2737_2739delAAG​(p.Lys913del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000184 in 1,548,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: KIF7 NM_198525.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_198525.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3	c.2737_2739delAAG	p.Lys913del	conservative_inframe_deletion	Exon 14 of 19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.2737_2739delAAG	p.Lys913del	conservative_inframe_deletion	Exon 14 of 19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000696512.1	c.2860_2862delAAG	p.Lys954del	conservative_inframe_deletion	Exon 14 of 19			ENSP00000512678.1
KIF7	ENST00000677187.1	n.411_413delAAG		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes AF: 0.000137 AC: 20 AN: 145722 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.000104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000180

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000159 AC: 39 AN: 245778 Hom.: 0 AF XY: 0.000165 AC XY: 22 AN XY: 133234

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000492

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.000170

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000189 AC: 265 AN: 1403080 Hom.: 0 AF XY: 0.000183 AC XY: 128 AN XY: 697666

Gnomad4 AFR exome AF: 0.0000956

Gnomad4 AMR exome AF: 0.0000460

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000212

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.000282

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.0000879

GnomAD4 genome AF: 0.000137 AC: 20 AN: 145722 Hom.: 0 Cov.: 30 AF XY: 0.000155 AC XY: 11 AN XY: 71036

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000202

Gnomad4 SAS AF: 0.000219

Gnomad4 FIN AF: 0.000104

Gnomad4 NFE AF: 0.000180

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000178

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 Uncertain:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 22, 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.2737_2739del, results in the deletion of 1 amino acid(s) of the KIF7 protein (p.Lys913del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769890385, gnomAD 0.05%). 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: 445340). 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. -

Intellectual disability Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs769890385; hg19: chr15-90176206;