15-89652777-C-A

Variant names:

• chr15-89652777-C-A
• rs8179065
• NM_198525.3:c.154G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198525.3(KIF7):​c.154G>T​(p.Asp52Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D52K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• Publications: 26 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.154G>T	p.Asp52Tyr	missense	Exon 2 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.154G>T	p.Asp52Tyr	missense	Exon 2 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000445906.1	TSL:1	n.154G>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000395906.1	F8WD21
	KIF7	ENST00000696512.1		c.277G>T	p.Asp93Tyr	missense	Exon 2 of 19	ENSP00000512678.1	A0A8Q3SIQ8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 13366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.50
MutPred		0.47		Gain of MoRF binding (P = 0.0723)
MVP		0.82
MPC		0.14
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.79
gMVP		0.65
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8179065; hg19: chr15-90196008;