rs932033181

Variant names:

• chr15-89648401-G-A
• rs932033181
• NM_198525.3:c.1297C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89648401-G-A
• chr15-89648401-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198525.3(KIF7):​c.1297C>T​(p.Pro433Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,002,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. P433T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0791814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3	c.1297C>T	p.Pro433Ser	missense_variant	Exon 5 of 19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.1297C>T	p.Pro433Ser	missense_variant	Exon 5 of 19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000696512.1	c.1420C>T	p.Pro474Ser	missense_variant	Exon 5 of 19			ENSP00000512678.1
KIF7	ENST00000445906.1	n.*956C>T		downstream_gene_variant		1		ENSP00000395906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000319 AC: 32 AN: 1002836 Hom.: 0 Cov.: 31 AF XY: 0.0000380 AC XY: 18 AN XY: 474050

African (AFR) AF: 0.00 AC: 0 AN: 19220

American (AMR) AF: 0.00 AC: 0 AN: 5366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10156

East Asian (EAS) AF: 0.00 AC: 0 AN: 16506

South Asian (SAS) AF: 0.0000423 AC: 1 AN: 23642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2448

European-Non Finnish (NFE) AF: 0.0000345 AC: 30 AN: 869090

Other (OTH) AF: 0.0000268 AC: 1 AN: 37378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.065
Sift	Benign	0.41	T
Sift4G	Benign	0.78	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.21		Gain of MoRF binding (P = 0.0453);
MVP		0.31
MPC		0.018
ClinPred		0.068	T
GERP RS		-0.37
Varity_R		0.059
gMVP		0.30
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs932033181; hg19: chr15-90191632;