15-89633008-TAGGGAGGG-TAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGG

Variant names:

• chr15-89633008-T-TAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGG
• rs3840030
• NM_198525.3:c.2719-13_2719-12insCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_198525.3(KIF7):​c.2719-13_2719-12insCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF7 NM_198525.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 15-89633008-T-TAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGG is Benign according to our data. Variant chr15-89633008-T-TAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGG is described in ClinVar as Likely_benign. ClinVar VariationId is 1634826.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2719-13_2719-12insCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		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_2719-12insCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		intron	N/A	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2842-13_2842-12insCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		intron	N/A	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2731-13_2731-12insCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCTCCCT		intron	N/A	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.0000153 AC: 2 AN: 130920 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000228

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000415 AC: 4 AN: 963598 Hom.: 0 Cov.: 22 AF XY: 0.00000405 AC XY: 2 AN XY: 494396

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000404 AC: 1 AN: 24772

American (AMR) AF: 0.00 AC: 0 AN: 39358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21722

East Asian (EAS) AF: 0.00 AC: 0 AN: 35712

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73750

European-Finnish (FIN) AF: 0.0000521 AC: 2 AN: 38376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 680954

Other (OTH) AF: 0.00 AC: 0 AN: 44360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000153 AC: 2 AN: 131026 Hom.: 0 Cov.: 0 AF XY: 0.0000158 AC XY: 1 AN XY: 63288

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 35650

American (AMR) AF: 0.00 AC: 0 AN: 13180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3122

East Asian (EAS) AF: 0.000228 AC: 1 AN: 4378

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8080

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59688

Other (OTH) AF: 0.00 AC: 0 AN: 1810

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Acrocallosal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.013

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;