chr15-89632975-ACTT-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K913K) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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]

KIF7 Gene-Disease associations (from GenCC):

• acrocallosal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hydrolethalus syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hydrolethalus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• multiple epiphyseal dysplasia, Al-Gazali type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_198525.3. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	NM_198525.3	MANE Select	c.2737_2739delAAG	p.Lys913del	conservative_inframe_deletion	Exon 14 of 19	NP_940927.2	Q2M1P5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	ENST00000394412.8	TSL:5 MANE Select	c.2737_2739delAAG	p.Lys913del	conservative_inframe_deletion	Exon 14 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2860_2862delAAG	p.Lys954del	conservative_inframe_deletion	Exon 14 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2749_2751delAAG	p.Lys917del	conservative_inframe_deletion	Exon 14 of 19	ENSP00000616259.1

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

GnomAD2 exomes AF: 0.000159 AC: 39 AN: 245778 AF XY: 0.000165

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 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

African (AFR) AF: 0.0000956 AC: 3 AN: 31372

American (AMR) AF: 0.0000460 AC: 2 AN: 43468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24266

East Asian (EAS) AF: 0.000212 AC: 8 AN: 37666

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85750

European-Finnish (FIN) AF: 0.000282 AC: 12 AN: 42568

Middle Eastern (MID) AF: 0.000362 AC: 2 AN: 5528

European-Non Finnish (NFE) AF: 0.000208 AC: 224 AN: 1075576

Other (OTH) AF: 0.0000879 AC: 5 AN: 56886

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

African (AFR) AF: 0.000130 AC: 5 AN: 38452

American (AMR) AF: 0.00 AC: 0 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4962

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4560

European-Finnish (FIN) AF: 0.000104 AC: 1 AN: 9612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.000180 AC: 12 AN: 66722

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000178

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Acrocallosal syndrome (1)
-	1	-	Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 (1)
-	-	1	Intellectual disability (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs769890385; hg19: chr15-90176206; COSMIC: COSV104571567; COSMIC: COSV104571567;