rs8179065

Variant names:

• chr15-89652777-C-T
• rs8179065
• NM_198525.3:c.154G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-89652777-C-T
• chr15-89652777-C-A

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.154G>A​(p.Asp52Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,551,448 control chromosomes in the GnomAD database, including 52,532 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D52K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (4112 hom., cov: 33)
  • Exomes 𝑓: 0.26 (48420 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.35
• Publications: 26 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• neurodevelopmental disorder

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=0.0028771162).
• BP6: Variant 15-89652777-C-T is Benign according to our data. Variant chr15-89652777-C-T is described in ClinVar as Benign. ClinVar VariationId is 129406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.352 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.154G>A	p.Asp52Asn	missense	Exon 2 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.154G>A	p.Asp52Asn	missense	Exon 2 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000445906.1	TSL:1	n.154G>A		non_coding_transcript_exon	Exon 2 of 5	ENSP00000395906.1	F8WD21
	KIF7	ENST00000696512.1		c.277G>A	p.Asp93Asn	missense	Exon 2 of 19	ENSP00000512678.1	A0A8Q3SIQ8

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32406 AN: 152170 Hom.: 4113 Cov.: 33

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.265 AC: 40742 AN: 153638 AF XY: 0.269

Gnomad AFR exome AF: 0.0646

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.263

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.259 AC: 362219 AN: 1399160 Hom.: 48420 Cov.: 45 AF XY: 0.261 AC XY: 180215 AN XY: 690112

African (AFR) AF: 0.0615 AC: 1942 AN: 31594

American (AMR) AF: 0.259 AC: 9237 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 6770 AN: 25178

East Asian (EAS) AF: 0.351 AC: 12538 AN: 35738

South Asian (SAS) AF: 0.309 AC: 24451 AN: 79226

European-Finnish (FIN) AF: 0.235 AC: 11544 AN: 49108

Middle Eastern (MID) AF: 0.293 AC: 1663 AN: 5682

European-Non Finnish (NFE) AF: 0.258 AC: 278686 AN: 1078928

Other (OTH) AF: 0.265 AC: 15388 AN: 58002

GnomAD4 genome AF: 0.213 AC: 32402 AN: 152288 Hom.: 4112 Cov.: 33 AF XY: 0.214 AC XY: 15929 AN XY: 74448

African (AFR) AF: 0.0765 AC: 3180 AN: 41584

American (AMR) AF: 0.243 AC: 3724 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 924 AN: 3472

East Asian (EAS) AF: 0.366 AC: 1890 AN: 5166

South Asian (SAS) AF: 0.309 AC: 1493 AN: 4832

European-Finnish (FIN) AF: 0.231 AC: 2450 AN: 10600

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17932 AN: 68012

Other (OTH) AF: 0.246 AC: 519 AN: 2114

Alfa AF: 0.249 Hom.: 13366

Bravo AF: 0.205

TwinsUK AF: 0.254 AC: 943

ALSPAC AF: 0.266 AC: 1026

ExAC AF: 0.203 AC: 5848

Asia WGS AF: 0.313 AC: 1089 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Acrocallosal syndrome (3)
-	-	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	0.086
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.097
Sift	Benign	0.11	T
Sift4G	Benign	0.063	T
Polyphen		0.014	B
Vest4		0.065
MPC		0.019
ClinPred		0.026	T
GERP RS		2.4
Varity_R		0.17
gMVP		0.37
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8179065; hg19: chr15-90196008; COSMIC: COSV67997245;