15-89629547-G-C

Variant names:

• chr15-89629547-G-C
• rs142032413
• NM_198525.3:c.3345C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198525.3(KIF7):​c.3345C>G​(p.His1115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,608,834 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1115L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 32)
  • Exomes 𝑓: 0.019 (336 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 2.12
• Publications: 13 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 (MetaRNN=0.0075957477).
• BP6: Variant 15-89629547-G-C is Benign according to our data. Variant chr15-89629547-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0155 (2356/152282) while in subpopulation NFE AF = 0.0222 (1508/68020). AF 95% confidence interval is 0.0212. There are 29 homozygotes in GnomAd4. There are 1172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.3345C>G	p.His1115Gln	missense	Exon 17 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.3345C>G	p.His1115Gln	missense	Exon 17 of 19	ENSP00000377934.3	Q2M1P5
	TICRR	ENST00000561095.1	TSL:1	n.*214G>C		non_coding_transcript_exon	Exon 4 of 4	ENSP00000453922.1	H0YN97
	TICRR	ENST00000561095.1	TSL:1	n.*214G>C		3_prime_UTR	Exon 4 of 4	ENSP00000453922.1	H0YN97

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2356 AN: 152164 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0160 AC: 3944 AN: 247252 AF XY: 0.0162

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0470

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0195 AC: 28345 AN: 1456552 Hom.: 336 Cov.: 37 AF XY: 0.0191 AC XY: 13821 AN XY: 724896

African (AFR) AF: 0.00284 AC: 95 AN: 33478

American (AMR) AF: 0.00387 AC: 173 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 338 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00517 AC: 446 AN: 86258

European-Finnish (FIN) AF: 0.0426 AC: 2052 AN: 48208

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0218 AC: 24274 AN: 1111946

Other (OTH) AF: 0.0157 AC: 948 AN: 60346

GnomAD4 genome AF: 0.0155 AC: 2356 AN: 152282 Hom.: 29 Cov.: 32 AF XY: 0.0157 AC XY: 1172 AN XY: 74466

African (AFR) AF: 0.00380 AC: 158 AN: 41560

American (AMR) AF: 0.00536 AC: 82 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4826

European-Finnish (FIN) AF: 0.0485 AC: 515 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1508 AN: 68020

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0103 Hom.: 2

Bravo AF: 0.0117

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0240 AC: 206

ExAC AF: 0.0168 AC: 2045

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0185

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Acrocallosal syndrome (2)
-	-	2	not provided (2)
-	-	1	Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 (1)
-	-	1	Hydrolethalus syndrome 2 (1)
-	1	-	Scoliosis, isolated, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.19
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.055	T
Polyphen		0.97	D
Vest4		0.18
MutPred		0.21		Gain of disorder (P = 0.0809)
MPC		0.11
ClinPred		0.016	T
GERP RS		5.1
Varity_R		0.52
gMVP		0.20
Mutation Taster		=79/21	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: rs142032413; hg19: chr15-90172778; COSMIC: COSV99076305; COSMIC: COSV99076305;