15-89630503-C-CAG

Position:

• chr15-89630503-C-CAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_198525.3(KIF7):​c.3112-11_3112-10insCT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,548,200 control chromosomes in the GnomAD database, including 253,302 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24302 hom., cov: 0)
  • Exomes 𝑓: 0.57 (229000 hom.)
• Consequence: KIF7 NM_198525.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.261

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]

TICRR (HGNC:28704): (TOPBP1 interacting checkpoint and replication regulator) Enables chromatin binding activity. Involved in regulation of DNA-dependent DNA replication initiation. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 15-89630503-C-CAG is Benign according to our data. Variant chr15-89630503-C-CAG is described in ClinVar as [Benign]. Clinvar id is 263145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.3112-11_3112-10insCT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.3112-11_3112-10insCT		splice_polypyrimidine_tract_variant, intron_variant		5	NM_198525.3	ENSP00000377934	P2
TICRR	ENST00000561095.1	c.*1170_*1171insAG		3_prime_UTR_variant, NMD_transcript_variant	4/4	1		ENSP00000453922
KIF7	ENST00000696512.1	c.3235-11_3235-10insCT		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000512678	A2
KIF7	ENST00000677187.1	n.786-11_786-10insCT		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85506 AN: 151820 Hom.: 24273 Cov.: 0

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.548

GnomAD3 exomes AF: 0.527 AC: 81910 AN: 155468 Hom.: 22281 AF XY: 0.528 AC XY: 43273 AN XY: 82018

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.533

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.498

Gnomad FIN exome AF: 0.611

Gnomad NFE exome AF: 0.585

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.570 AC: 795399 AN: 1396262 Hom.: 229000 Cov.: 30 AF XY: 0.568 AC XY: 391080 AN XY: 688922

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.538

Gnomad4 EAS exome AF: 0.308

Gnomad4 SAS exome AF: 0.504

Gnomad4 FIN exome AF: 0.610

Gnomad4 NFE exome AF: 0.588

Gnomad4 OTH exome AF: 0.549

GnomAD4 genome AF: 0.563 AC: 85580 AN: 151938 Hom.: 24302 Cov.: 0 AF XY: 0.559 AC XY: 41544 AN XY: 74256

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.612

Gnomad4 NFE AF: 0.585

Gnomad4 OTH AF: 0.547

Alfa AF: 0.500 Hom.: 2439

Bravo AF: 0.553

Asia WGS AF: 0.424 AC: 1476 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Acrocallosal syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Hydrolethalus syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2018

- -

Multiple epiphyseal dysplasia, Al-Gazali type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35820949; hg19: chr15-90173734;