chr15-89628477-C-G

Variant names:

• chr15-89628477-C-G
• rs73477443
• NM_198525.3:c.3974G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198525.3(KIF7):​c.3974G>C​(p.Arg1325Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1325Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.94
• 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]

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	NM_198525.3	MANE Select	c.3974G>C	p.Arg1325Pro	missense	Exon 19 of 19	NP_940927.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	ENST00000394412.8	TSL:5 MANE Select	c.3974G>C	p.Arg1325Pro	missense	Exon 19 of 19	ENSP00000377934.3
	TICRR	ENST00000561095.1	TSL:1	n.*97-953C>G		intron	N/A	ENSP00000453922.1
	KIF7	ENST00000696512.1		c.4097G>C	p.Arg1366Pro	missense	Exon 19 of 19	ENSP00000512678.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459014 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725596

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110790

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.9
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.44		Loss of MoRF binding (P = 0.0021)
MVP		0.90
MPC		0.14
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.48
Mutation Taster		=29/71	disease causing

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: rs73477443; hg19: chr15-90171708;