NM_198525.3:c.1177G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198525.3(KIF7):c.1177G>T(p.Gly393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,132,710 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 6 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 2.02

Publications

0 publications found

Variant links:

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

KIF7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003365159).

BP6

Variant 15-89648521-C-A is Benign according to our data. Variant chr15-89648521-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283923.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000422 (62/146944) while in subpopulation SAS AF = 0.0104 (50/4816). AF 95% confidence interval is 0.00809. There are 3 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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.1177G>T	p.Gly393Cys	missense	Exon 5 of 19	NP_940927.2	Q2M1P5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF7	ENST00000394412.8	TSL:5 MANE Select	c.1177G>T	p.Gly393Cys	missense	Exon 5 of 19	ENSP00000377934.3	Q2M1P5
KIF7	ENST00000445906.1	TSL:1	n.*836G>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000395906.1	F8WD21
KIF7	ENST00000445906.1	TSL:1	n.*836G>T		3_prime_UTR	Exon 5 of 5	ENSP00000395906.1	F8WD21

Frequencies

GnomAD3 genomes

AF:

0.000409

AC:

AN:

146856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00995

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000106

Gnomad OTH

AF:

0.000986

GnomAD2 exomes

AF:

0.00211

AC:

AN:

2370

AF XY:

0.00324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000338

AC:

333

AN:

985766

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

224

AN XY:

469190

show subpopulations

African (AFR)

AF:

0.0000554

AC:

AN:

18058

American (AMR)

AF:

0.000227

AC:

AN:

4404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8950

East Asian (EAS)

AF:

0.00

AC:

AN:

13626

South Asian (SAS)

AF:

0.00876

AC:

257

AN:

29328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17600

Middle Eastern (MID)

AF:

0.00460

AC:

AN:

2390

European-Non Finnish (NFE)

AF:

0.0000456

AC:

AN:

855842

Other (OTH)

AF:

0.000675

AC:

AN:

35568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000422

AC:

AN:

146944

Hom.:

Cov.:

AF XY:

0.000601

AC XY:

AN XY:

71558

show subpopulations

African (AFR)

AF:

0.0000487

AC:

AN:

41038

American (AMR)

AF:

0.00

AC:

AN:

14794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.000196

AC:

AN:

5102

South Asian (SAS)

AF:

0.0104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000106

AC:

AN:

66058

Other (OTH)

AF:

0.000978

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.00228

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Acrocallosal syndrome (2)

Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 (1)

Inborn genetic diseases (1)

Acrocallosal syndrome;C2931104:Hydrolethalus syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.24

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

PhyloP100

2.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.3

REVEL

Benign

0.17

Sift

Benign

0.13

Sift4G

Benign

0.066

Polyphen

0.0

Vest4

0.16

MutPred

0.27

Gain of helix (P = 0.0128)

MVP

0.35

MPC

0.018

ClinPred

0.032

GERP RS

1.5

Varity_R

0.11

gMVP

0.38

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over