rs74251725

Variant names:

• chr15-89629369-G-A
• rs74251725
• NM_198525.3:c.3517+6C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89629369-G-A
• chr15-89629369-G-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.3517+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,583,102 control chromosomes in the GnomAD database, including 82,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5835 hom., cov: 28)
  • Exomes 𝑓: 0.32 (76748 hom.)
• Consequence: KIF7 NM_198525.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001589
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.304
• Publications: 9 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]

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-89629369-G-A is Benign according to our data. Variant chr15-89629369-G-A is described in ClinVar as Benign. ClinVar VariationId is 129416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 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.3517+6C>T		splice_region 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.3517+6C>T		splice_region intron	N/A	ENSP00000377934.3	Q2M1P5
	TICRR	ENST00000561095.1	TSL:1	n.*97-61G>A		intron	N/A	ENSP00000453922.1	H0YN97
	KIF7	ENST00000696512.1		c.3640+6C>T		splice_region intron	N/A	ENSP00000512678.1	A0A8Q3SIQ8

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39296 AN: 150468 Hom.: 5835 Cov.: 28

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.298

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.289

GnomAD2 exomes AF: 0.308 AC: 71590 AN: 232426 AF XY: 0.316

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.355

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.324 AC: 463632 AN: 1432522 Hom.: 76748 Cov.: 35 AF XY: 0.326 AC XY: 232044 AN XY: 711154

African (AFR) AF: 0.101 AC: 3355 AN: 33276

American (AMR) AF: 0.285 AC: 12631 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 7685 AN: 25442

East Asian (EAS) AF: 0.340 AC: 13410 AN: 39408

South Asian (SAS) AF: 0.369 AC: 31313 AN: 84752

European-Finnish (FIN) AF: 0.275 AC: 11044 AN: 40108

Middle Eastern (MID) AF: 0.380 AC: 1622 AN: 4274

European-Non Finnish (NFE) AF: 0.330 AC: 363272 AN: 1101460

Other (OTH) AF: 0.324 AC: 19300 AN: 59490

GnomAD4 genome AF: 0.261 AC: 39296 AN: 150580 Hom.: 5835 Cov.: 28 AF XY: 0.261 AC XY: 19194 AN XY: 73460

African (AFR) AF: 0.113 AC: 4650 AN: 41148

American (AMR) AF: 0.279 AC: 4210 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1011 AN: 3442

East Asian (EAS) AF: 0.343 AC: 1724 AN: 5028

South Asian (SAS) AF: 0.366 AC: 1722 AN: 4706

European-Finnish (FIN) AF: 0.269 AC: 2785 AN: 10370

Middle Eastern (MID) AF: 0.286 AC: 83 AN: 290

European-Non Finnish (NFE) AF: 0.329 AC: 22211 AN: 67516

Other (OTH) AF: 0.287 AC: 599 AN: 2090

Alfa AF: 0.301 Hom.: 1467

Bravo AF: 0.254

Asia WGS AF: 0.333 AC: 1153 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.82
CADD	Benign	7.4
DANN	Benign	0.79
PhyloP100		0.30
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0040
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: rs74251725; hg19: chr15-90172600; COSMIC: COSV51544315; COSMIC: COSV51544315;