15-89648509-C-T

Position:

• chr15-89648509-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198525.3(KIF7):​c.1189G>A​(p.Ala397Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,067,280 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (12 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.515

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044965744).
• BP6: Variant 15-89648509-C-T is Benign according to our data. Variant chr15-89648509-C-T is described in ClinVar as [Benign]. Clinvar id is 282376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00829 (1216/146700) while in subpopulation AFR AF= 0.0282 (1154/40994). AF 95% confidence interval is 0.0268. There are 18 homozygotes in gnomad4. There are 578 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.1189G>A	p.Ala397Thr	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.1189G>A	p.Ala397Thr	missense_variant	5/19	5	NM_198525.3	ENSP00000377934	P2
KIF7	ENST00000445906.1	c.*848G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1		ENSP00000395906
KIF7	ENST00000696512.1	c.1312G>A	p.Ala438Thr	missense_variant	5/19			ENSP00000512678	A2

Frequencies

GnomAD3 genomes AF: 0.00826 AC: 1211 AN: 146610 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00312

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000758

Gnomad OTH AF: 0.00445

GnomAD4 exome AF: 0.000684 AC: 630 AN: 920580 Hom.: 12 Cov.: 30 AF XY: 0.000678 AC XY: 293 AN XY: 432134

Gnomad4 AFR exome AF: 0.0303

Gnomad4 AMR exome AF: 0.00341

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: 0.0000392

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00829 AC: 1216 AN: 146700 Hom.: 18 Cov.: 32 AF XY: 0.00809 AC XY: 578 AN XY: 71440

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.00311

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000758

Gnomad4 OTH AF: 0.00441

Alfa AF: 0.00603 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Acrocallosal syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.017
Sift	Benign	0.16	T
Sift4G	Benign	0.18	T
Polyphen		0.0080	B
Vest4		0.034
MVP		0.25
MPC		0.018
ClinPred		0.078	T
GERP RS		1.1
Varity_R		0.031
gMVP		0.27

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: rs535621809; hg19: chr15-90191740;