rs138354681

Variant names:

• chr15-89633777-T-C
• rs138354681
• NM_198525.3:c.2501A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198525.3(KIF7):​c.2501A>G​(p.Gln834Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,611,624 control chromosomes in the GnomAD database, including 24 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 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (24 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 7.94
• Publications: 20 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020664513).
• BP6: Variant 15-89633777-T-C is Benign according to our data. Variant chr15-89633777-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252807.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00302 (460/152368) while in subpopulation NFE AF = 0.00559 (380/68026). AF 95% confidence interval is 0.00512. There are 0 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 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.2501A>G	p.Gln834Arg	missense	Exon 12 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.2501A>G	p.Gln834Arg	missense	Exon 12 of 19	ENSP00000377934.3
	KIF7	ENST00000696512.1		c.2624A>G	p.Gln875Arg	missense	Exon 12 of 19	ENSP00000512678.1
	KIF7	ENST00000946200.1		c.2513A>G	p.Gln838Arg	missense	Exon 12 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00327 AC: 814 AN: 249166 AF XY: 0.00339

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000960

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00466 AC: 6798 AN: 1459256 Hom.: 24 Cov.: 33 AF XY: 0.00463 AC XY: 3365 AN XY: 726088

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00208 AC: 93 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00321 AC: 84 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00368 AC: 317 AN: 86246

European-Finnish (FIN) AF: 0.00122 AC: 62 AN: 50870

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

European-Non Finnish (NFE) AF: 0.00529 AC: 5880 AN: 1111976

Other (OTH) AF: 0.00532 AC: 321 AN: 60370

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.00248 AC XY: 185 AN XY: 74524

African (AFR) AF: 0.000625 AC: 26 AN: 41600

American (AMR) AF: 0.000915 AC: 14 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00559 AC: 380 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00436 Hom.: 8

Bravo AF: 0.00292

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00320 AC: 388

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00468

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.24
Sift	Benign	0.034	D
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.67
MVP		0.59
MPC		0.15
ClinPred		0.0038	T
GERP RS		5.1
Varity_R		0.64
gMVP		0.42
Mutation Taster		=84/16	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: rs138354681; hg19: chr15-90177008; COSMIC: COSV67997653; COSMIC: COSV67997653;