rs141028210

Variant names:

• chr15-89628491-A-T
• rs141028210
• NM_198525.3:c.3960T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_198525.3(KIF7):​c.3960T>A​(p.Pro1320Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,612,264 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (5 hom.)
• Consequence: KIF7 NM_198525.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.299
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-89628491-A-T is Benign according to our data. Variant chr15-89628491-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263153.
• BP7: Synonymous conserved (PhyloP=-0.299 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000932 (142/152302) while in subpopulation NFE AF = 0.00159 (108/68008). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.3960T>A	p.Pro1320Pro	synonymous	Exon 19 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.3960T>A	p.Pro1320Pro	synonymous	Exon 19 of 19	ENSP00000377934.3	Q2M1P5
	TICRR	ENST00000561095.1	TSL:1	n.*97-939A>T		intron	N/A	ENSP00000453922.1	H0YN97
	KIF7	ENST00000696512.1		c.4083T>A	p.Pro1361Pro	synonymous	Exon 19 of 19	ENSP00000512678.1	A0A8Q3SIQ8

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000882 AC: 219 AN: 248408 AF XY: 0.000942

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00102 AC: 1493 AN: 1459962 Hom.: 5 Cov.: 32 AF XY: 0.00101 AC XY: 735 AN XY: 726164

African (AFR) AF: 0.000329 AC: 11 AN: 33444

American (AMR) AF: 0.000851 AC: 38 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86212

European-Finnish (FIN) AF: 0.0000954 AC: 5 AN: 52394

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.00118 AC: 1312 AN: 1111428

Other (OTH) AF: 0.00147 AC: 89 AN: 60340

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74480

African (AFR) AF: 0.000241 AC: 10 AN: 41578

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00101

EpiCase AF: 0.00267

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Acrocallosal syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.74
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism

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: rs141028210; hg19: chr15-90171722;