rs587780374

Positions:

• chr15-89648539-G-C
• chr15-89648539-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198525.3(KIF7):​c.1159C>G​(p.Arg387Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000179 in 1,119,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35779005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.1159C>G	p.Arg387Gly	missense_variant	5/19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.1159C>G	p.Arg387Gly	missense_variant	5/19	5	NM_198525.3	ENSP00000377934	P2
KIF7	ENST00000445906.1	c.*818C>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	1		ENSP00000395906
KIF7	ENST00000696512.1	c.1282C>G	p.Arg428Gly	missense_variant	5/19			ENSP00000512678	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000179 AC: 2 AN: 1119716 Hom.: 0 Cov.: 27 AF XY: 0.00000367 AC XY: 2 AN XY: 544350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000207

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.0016
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.15
Sift	Benign	0.14	T
Sift4G	Benign	0.31	T
Polyphen		0.56	P
Vest4		0.35
MutPred		0.17		Gain of methylation at R389 (P = 0.1038);
MVP		0.75
MPC		0.16
ClinPred		0.75	D
GERP RS		3.5
Varity_R		0.31
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780374; hg19: chr15-90191770;