15-89648478-G-T

Position:

• chr15-89648478-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198525.3(KIF7):​c.1220C>A​(p.Ala407Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000569 in 1,044,806 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.84

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053034514).
• BP6: Variant 15-89648478-G-T is Benign according to our data. Variant chr15-89648478-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129404.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr15-89648478-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000248 (223/898154) while in subpopulation AFR AF= 0.0116 (194/16710). AF 95% confidence interval is 0.0103. There are 2 homozygotes in gnomad4_exome. There are 102 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.1220C>A	p.Ala407Asp	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.1220C>A	p.Ala407Asp	missense_variant	5/19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000696512.1	c.1343C>A	p.Ala448Asp	missense_variant	5/19			ENSP00000512678.1
KIF7	ENST00000445906.1	n.*879C>A		downstream_gene_variant		1		ENSP00000395906.1

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 365 AN: 146560 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00843

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000949

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: 0.0000303

Gnomad OTH AF: 0.00198

GnomAD4 exome AF: 0.000248 AC: 223 AN: 898154 Hom.: 2 Cov.: 31 AF XY: 0.000243 AC XY: 102 AN XY: 419684

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000723

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000125

Gnomad4 OTH exome AF: 0.000840

GnomAD4 genome AF: 0.00254 AC: 372 AN: 146652 Hom.: 1 Cov.: 32 AF XY: 0.00231 AC XY: 165 AN XY: 71396

Gnomad4 AFR AF: 0.00858

Gnomad4 AMR AF: 0.000948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000303

Gnomad4 OTH AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29915382) -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2020

Variant summary: KIF7 c.1220C>A (p.Ala407Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 137568 control chromosomes, predominantly at a frequency of 0.0084 within the African or African-American subpopulation in the gnomAD database (v3 genomes dataset), including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in KIF7 causing Acrocallosal Syndrome/Joubert Syndrome 12 phenotype (0.0004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1220C>A has been reported in the literature in one individual affected with cerebellar ataxia (Sun_2019). This report did not provide unequivocal conclusions about association of the variant with Acrocallosal Syndrome/Joubert Syndrome 12. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Acrocallosal syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.38	T
Polyphen		0.54	P
Vest4		0.19
MVP		0.72
MPC		0.050
ClinPred		0.60	D
GERP RS		3.9
Varity_R		0.44
gMVP		0.77

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: rs587780375; hg19: chr15-90191709;