rs764430327

Variant names:

• chr15-89632980-T-C
• rs764430327
• NM_198525.3:c.2735A>G
• KIF7 p.Lys912Arg

Your query was ambiguous. Multiple possible variants found:

• chr15-89632980-T-C
• chr15-89632980-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198525.3(KIF7):​c.2735A>G​(p.Lys912Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,351,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K912K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.18
• 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3556634).

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.2735A>G	p.Lys912Arg	missense	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.2735A>G	p.Lys912Arg	missense	Exon 14 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2858A>G	p.Lys953Arg	missense	Exon 14 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2747A>G	p.Lys916Arg	missense	Exon 14 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 143472 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000327 AC: 8 AN: 244852 AF XY: 0.0000301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000192 AC: 26 AN: 1351680 Hom.: 0 Cov.: 53 AF XY: 0.0000149 AC XY: 10 AN XY: 672428

African (AFR) AF: 0.00 AC: 0 AN: 30218

American (AMR) AF: 0.0000705 AC: 3 AN: 42556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22718

East Asian (EAS) AF: 0.00 AC: 0 AN: 35792

South Asian (SAS) AF: 0.00 AC: 0 AN: 85160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39408

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5374

European-Non Finnish (NFE) AF: 0.0000203 AC: 21 AN: 1036436

Other (OTH) AF: 0.0000185 AC: 1 AN: 54018

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 143472 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 69678

African (AFR) AF: 0.00 AC: 0 AN: 37878

American (AMR) AF: 0.00 AC: 0 AN: 14524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 4930

South Asian (SAS) AF: 0.00 AC: 0 AN: 4512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65832

Other (OTH) AF: 0.00 AC: 0 AN: 1988

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.32
Mutation Taster		=60/40	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs764430327;

hg19: chr15-90176211;