15-89646817-A-G

Variant names:

• chr15-89646817-A-G
• rs1110060
• NM_198525.3:c.1788+13T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198525.3(KIF7):​c.1788+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,612,020 control chromosomes in the GnomAD database, including 294,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26907 hom., cov: 31)
  • Exomes 𝑓: 0.60 (267683 hom.)
• Consequence: KIF7 NM_198525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.76
• Publications: 17 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hydrolethalus syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-89646817-A-G is Benign according to our data. Variant chr15-89646817-A-G is described in ClinVar as Benign. ClinVar VariationId is 263138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	NM_198525.3	MANE Select	c.1788+13T>C		intron	N/A	NP_940927.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	ENST00000394412.8	TSL:5 MANE Select	c.1788+13T>C		intron	N/A	ENSP00000377934.3
	KIF7	ENST00000696512.1		c.1911+13T>C		intron	N/A	ENSP00000512678.1
	KIF7	ENST00000946200.1		c.1803+13T>C		intron	N/A	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89796 AN: 151668 Hom.: 26878 Cov.: 31

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.564

GnomAD2 exomes AF: 0.560 AC: 140214 AN: 250600 AF XY: 0.562

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.439

Gnomad ASJ exome AF: 0.562

Gnomad EAS exome AF: 0.357

Gnomad FIN exome AF: 0.625

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.571

GnomAD4 exome AF: 0.602 AC: 878687 AN: 1460234 Hom.: 267683 Cov.: 39 AF XY: 0.599 AC XY: 435368 AN XY: 726522

African (AFR) AF: 0.619 AC: 20701 AN: 33428

American (AMR) AF: 0.447 AC: 19967 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14709 AN: 26130

East Asian (EAS) AF: 0.340 AC: 13509 AN: 39690

South Asian (SAS) AF: 0.502 AC: 43265 AN: 86220

European-Finnish (FIN) AF: 0.627 AC: 33489 AN: 53388

Middle Eastern (MID) AF: 0.524 AC: 2766 AN: 5278

European-Non Finnish (NFE) AF: 0.625 AC: 694961 AN: 1111092

Other (OTH) AF: 0.586 AC: 35320 AN: 60294

GnomAD4 genome AF: 0.592 AC: 89870 AN: 151786 Hom.: 26907 Cov.: 31 AF XY: 0.589 AC XY: 43705 AN XY: 74154

African (AFR) AF: 0.616 AC: 25511 AN: 41386

American (AMR) AF: 0.505 AC: 7707 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1911 AN: 3468

East Asian (EAS) AF: 0.368 AC: 1878 AN: 5110

South Asian (SAS) AF: 0.479 AC: 2302 AN: 4802

European-Finnish (FIN) AF: 0.629 AC: 6638 AN: 10548

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42001 AN: 67900

Other (OTH) AF: 0.561 AC: 1183 AN: 2108

Alfa AF: 0.600 Hom.: 43758

Bravo AF: 0.584

Asia WGS AF: 0.437 AC: 1521 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Acrocallosal syndrome (3)
-	-	2	not provided (2)
-	-	1	Hydrolethalus syndrome 2 (1)
-	-	1	Multiple epiphyseal dysplasia, Al-Gazali type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.017
DANN	Benign	0.72
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1110060; hg19: chr15-90190048; COSMIC: COSV67997898; COSMIC: COSV67997898;