15-89633008-TAGGGAGGG-TAGGGAGGGAGGG

Variant names:

• chr15-89633008-T-TAGGG
• rs3840030
• NM_198525.3:c.2719-16_2719-13dupCCCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_198525.3(KIF7):​c.2719-16_2719-13dupCCCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,094,574 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (37 hom.)
• Consequence: KIF7 NM_198525.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0130
• Publications: 1 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: 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-89633008-T-TAGGG is Benign according to our data. Variant chr15-89633008-T-TAGGG is described in ClinVar as Likely_benign. ClinVar VariationId is 418626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00174 (228/131024) while in subpopulation NFE AF = 0.00261 (156/59686). AF 95% confidence interval is 0.00228. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 37 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.2719-16_2719-13dupCCCT		intron	N/A	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.2719-13_2719-12insCCCT		intron	N/A	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2842-13_2842-12insCCCT		intron	N/A	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2731-13_2731-12insCCCT		intron	N/A	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 228 AN: 130918 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000788

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00320

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00261

Gnomad OTH AF: 0.00279

GnomAD4 exome AF: 0.00243 AC: 2338 AN: 963550 Hom.: 37 Cov.: 22 AF XY: 0.00243 AC XY: 1203 AN XY: 494366

African (AFR) AF: 0.000565 AC: 14 AN: 24768

American (AMR) AF: 0.000991 AC: 39 AN: 39358

Ashkenazi Jewish (ASJ) AF: 0.00424 AC: 92 AN: 21722

East Asian (EAS) AF: 0.000224 AC: 8 AN: 35714

South Asian (SAS) AF: 0.000298 AC: 22 AN: 73754

European-Finnish (FIN) AF: 0.00122 AC: 47 AN: 38372

Middle Eastern (MID) AF: 0.00131 AC: 6 AN: 4592

European-Non Finnish (NFE) AF: 0.00292 AC: 1991 AN: 680916

Other (OTH) AF: 0.00268 AC: 119 AN: 44354

GnomAD4 genome AF: 0.00174 AC: 228 AN: 131024 Hom.: 0 Cov.: 0 AF XY: 0.00160 AC XY: 101 AN XY: 63286

African (AFR) AF: 0.000785 AC: 28 AN: 35650

American (AMR) AF: 0.00144 AC: 19 AN: 13180

Ashkenazi Jewish (ASJ) AF: 0.00320 AC: 10 AN: 3122

East Asian (EAS) AF: 0.00 AC: 0 AN: 4378

South Asian (SAS) AF: 0.000246 AC: 1 AN: 4072

European-Finnish (FIN) AF: 0.00111 AC: 9 AN: 8080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.00261 AC: 156 AN: 59686

Other (OTH) AF: 0.00276 AC: 5 AN: 1810

Alfa AF: 0.00159 Hom.: 1558

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Acrocallosal syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.013
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3840030; hg19: chr15-90176239;