rs138410949

Variant names:

• chr15-89631625-T-C
• rs138410949
• NM_198525.3:c.2981A>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.2981A>G​(p.Gln994Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00269 in 1,561,306 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q994H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0028 (8 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:4
• Conservation: PhyloP100: 3.79
• Publications: 12 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=0.008629203).
• BP6: Variant 15-89631625-T-C is Benign according to our data. Variant chr15-89631625-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194572.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00202 (307/152324) while in subpopulation AMR AF = 0.00477 (73/15308). AF 95% confidence interval is 0.00389. There are 1 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	NM_198525.3	MANE Select	c.2981A>G	p.Gln994Arg	missense	Exon 15 of 19	NP_940927.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	ENST00000394412.8	TSL:5 MANE Select	c.2981A>G	p.Gln994Arg	missense	Exon 15 of 19	ENSP00000377934.3
	KIF7	ENST00000696512.1		c.3104A>G	p.Gln1035Arg	missense	Exon 15 of 19	ENSP00000512678.1
	KIF7	ENST00000946200.1		c.2993A>G	p.Gln998Arg	missense	Exon 15 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152206 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00164 AC: 278 AN: 169278 AF XY: 0.00156

Gnomad AFR exome AF: 0.000942

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000506

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00276 AC: 3894 AN: 1408982 Hom.: 8 Cov.: 39 AF XY: 0.00256 AC XY: 1780 AN XY: 696186

African (AFR) AF: 0.000782 AC: 25 AN: 31964

American (AMR) AF: 0.00340 AC: 129 AN: 37992

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 36422

South Asian (SAS) AF: 0.0000374 AC: 3 AN: 80300

European-Finnish (FIN) AF: 0.00118 AC: 58 AN: 49098

Middle Eastern (MID) AF: 0.000875 AC: 5 AN: 5716

European-Non Finnish (NFE) AF: 0.00323 AC: 3499 AN: 1083806

Other (OTH) AF: 0.00298 AC: 174 AN: 58298

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152324 Hom.: 1 Cov.: 34 AF XY: 0.00196 AC XY: 146 AN XY: 74494

African (AFR) AF: 0.000770 AC: 32 AN: 41580

American (AMR) AF: 0.00477 AC: 73 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 68032

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0305 Hom.: 6393

Bravo AF: 0.00226

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00164 AC: 14

ExAC AF: 0.000806 AC: 94

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
1	-	2	Acrocallosal syndrome (3)
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.086
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Benign	0.063	T
Sift4G	Benign	0.26	T
Polyphen		0.0070	B
Vest4		0.20
MVP		0.42
MPC		0.019
ClinPred		0.024	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.10
Mutation Taster		=97/3	disease causing (ClinVar)

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: rs138410949; hg19: chr15-90174856;