rs62021460

Variant names:

• chr15-89652935-A-C
• rs62021460
• NM_198525.3:c.-5T>G

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.-5T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,507,096 control chromosomes in the GnomAD database, including 2,058 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (149 hom., cov: 33)
  • Exomes 𝑓: 0.051 (1909 hom.)
• Consequence: KIF7 NM_198525.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.362
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-89652935-A-C is Benign according to our data. Variant chr15-89652935-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0879 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	NM_198525.3	MANE Select	c.-5T>G		5_prime_UTR	Exon 2 of 19	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.-5T>G		5_prime_UTR	Exon 2 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000445906.1	TSL:1	n.-5T>G		non_coding_transcript_exon	Exon 2 of 5	ENSP00000395906.1	F8WD21
	KIF7	ENST00000445906.1	TSL:1	n.-5T>G		5_prime_UTR	Exon 2 of 5	ENSP00000395906.1	F8WD21

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6117 AN: 152146 Hom.: 148 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.0397

GnomAD2 exomes AF: 0.0483 AC: 5738 AN: 118826 AF XY: 0.0476

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0600

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0509 AC: 68952 AN: 1354832 Hom.: 1909 Cov.: 34 AF XY: 0.0506 AC XY: 33574 AN XY: 663094

African (AFR) AF: 0.0112 AC: 348 AN: 31014

American (AMR) AF: 0.0363 AC: 1249 AN: 34368

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 1371 AN: 23310

East Asian (EAS) AF: 0.0878 AC: 3089 AN: 35202

South Asian (SAS) AF: 0.0334 AC: 2504 AN: 74882

European-Finnish (FIN) AF: 0.0443 AC: 1692 AN: 38214

Middle Eastern (MID) AF: 0.0516 AC: 243 AN: 4708

European-Non Finnish (NFE) AF: 0.0529 AC: 55906 AN: 1056876

Other (OTH) AF: 0.0453 AC: 2550 AN: 56258

GnomAD4 genome AF: 0.0402 AC: 6119 AN: 152264 Hom.: 149 Cov.: 33 AF XY: 0.0394 AC XY: 2935 AN XY: 74458

African (AFR) AF: 0.0135 AC: 560 AN: 41566

American (AMR) AF: 0.0377 AC: 576 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3470

East Asian (EAS) AF: 0.0948 AC: 490 AN: 5168

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4820

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10616

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0538 AC: 3658 AN: 68008

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0481 Hom.: 53

Bravo AF: 0.0397

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Acrocallosal syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs62021460; hg19: chr15-90196166;