15-89632842-C-A

Variant names:

• chr15-89632842-C-A
• rs3803530
• NM_198525.3:c.2873G>T

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.2873G>T​(p.Ser958Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,605,504 control chromosomes in the GnomAD database, including 253,262 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20936 hom., cov: 31)
  • Exomes 𝑓: 0.56 (232326 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.13
• Publications: 32 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hydrolethalus syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 (MetaRNN=2.8204651E-5).
• BP6: Variant 15-89632842-C-A is Benign according to our data. Variant chr15-89632842-C-A is described in ClinVar as Benign. ClinVar VariationId is 96651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.577 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.2873G>T	p.Ser958Ile	missense	Exon 14 of 19	NP_940927.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	ENST00000394412.8	TSL:5 MANE Select	c.2873G>T	p.Ser958Ile	missense	Exon 14 of 19	ENSP00000377934.3
	KIF7	ENST00000696512.1		c.2996G>T	p.Ser999Ile	missense	Exon 14 of 19	ENSP00000512678.1
	KIF7	ENST00000946200.1		c.2885G>T	p.Ser962Ile	missense	Exon 14 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79003 AN: 151658 Hom.: 20918 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.509

GnomAD2 exomes AF: 0.515 AC: 124854 AN: 242292 AF XY: 0.520

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.541

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.604

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.562 AC: 816529 AN: 1453728 Hom.: 232326 Cov.: 65 AF XY: 0.560 AC XY: 404995 AN XY: 723106

African (AFR) AF: 0.444 AC: 14852 AN: 33464

American (AMR) AF: 0.416 AC: 18448 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 14146 AN: 26036

East Asian (EAS) AF: 0.310 AC: 12309 AN: 39670

South Asian (SAS) AF: 0.496 AC: 42522 AN: 85738

European-Finnish (FIN) AF: 0.607 AC: 28968 AN: 47734

Middle Eastern (MID) AF: 0.451 AC: 2506 AN: 5552

European-Non Finnish (NFE) AF: 0.586 AC: 650448 AN: 1110898

Other (OTH) AF: 0.537 AC: 32330 AN: 60256

GnomAD4 genome AF: 0.521 AC: 79059 AN: 151776 Hom.: 20936 Cov.: 31 AF XY: 0.519 AC XY: 38523 AN XY: 74220

African (AFR) AF: 0.448 AC: 18546 AN: 41390

American (AMR) AF: 0.453 AC: 6922 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1860 AN: 3464

East Asian (EAS) AF: 0.336 AC: 1731 AN: 5154

South Asian (SAS) AF: 0.471 AC: 2261 AN: 4800

European-Finnish (FIN) AF: 0.612 AC: 6475 AN: 10578

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39485 AN: 67808

Other (OTH) AF: 0.509 AC: 1072 AN: 2108

Alfa AF: 0.555 Hom.: 80453

Bravo AF: 0.505

TwinsUK AF: 0.585 AC: 2168

ALSPAC AF: 0.581 AC: 2240

ESP6500AA AF: 0.466 AC: 2051

ESP6500EA AF: 0.574 AC: 4933

ExAC AF: 0.523 AC: 63524

Asia WGS AF: 0.413 AC: 1440 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Acrocallosal syndrome (4)
-	-	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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.000028	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.29	N
PhyloP100		1.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.098
Sift	Benign	0.28	T
Sift4G	Benign	0.32	T
Polyphen		0.0030	B
Vest4		0.084
MPC		0.021
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.15
Mutation Taster		=87/13	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: rs3803530; hg19: chr15-90176073; COSMIC: COSV51539255; COSMIC: COSV51539255;