rs12900805

Variant names:

• chr15-89631593-C-T
• rs12900805
• NM_198525.3:c.3013G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-89631593-C-T
• chr15-89631593-C-A
• chr15-89631593-C-G

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.3013G>A​(p.Gly1005Arg) 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 1,561,492 control chromosomes in the GnomAD database, including 246,566 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21072 hom., cov: 34)
  • Exomes 𝑓: 0.56 (225494 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.19
• Publications: 29 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=1.1864759E-5).
• BP6: Variant 15-89631593-C-T is Benign according to our data. Variant chr15-89631593-C-T is described in ClinVar as Benign. ClinVar VariationId is 96653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 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.3013G>A	p.Gly1005Arg	missense	Exon 15 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.3013G>A	p.Gly1005Arg	missense	Exon 15 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.3136G>A	p.Gly1046Arg	missense	Exon 15 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.3025G>A	p.Gly1009Arg	missense	Exon 15 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79297 AN: 151976 Hom.: 21054 Cov.: 34

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.500 AC: 85815 AN: 171570 AF XY: 0.503

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.534

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.604

Gnomad NFE exome AF: 0.561

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.562 AC: 791872 AN: 1409398 Hom.: 225494 Cov.: 50 AF XY: 0.560 AC XY: 389975 AN XY: 696490

African (AFR) AF: 0.440 AC: 14120 AN: 32056

American (AMR) AF: 0.410 AC: 15631 AN: 38116

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 13741 AN: 25362

East Asian (EAS) AF: 0.303 AC: 11112 AN: 36716

South Asian (SAS) AF: 0.499 AC: 40074 AN: 80232

European-Finnish (FIN) AF: 0.608 AC: 29785 AN: 48954

Middle Eastern (MID) AF: 0.455 AC: 2574 AN: 5658

European-Non Finnish (NFE) AF: 0.585 AC: 633703 AN: 1084004

Other (OTH) AF: 0.534 AC: 31132 AN: 58300

GnomAD4 genome AF: 0.522 AC: 79353 AN: 152094 Hom.: 21072 Cov.: 34 AF XY: 0.520 AC XY: 38659 AN XY: 74348

African (AFR) AF: 0.448 AC: 18602 AN: 41490

American (AMR) AF: 0.453 AC: 6933 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1867 AN: 3472

East Asian (EAS) AF: 0.336 AC: 1727 AN: 5138

South Asian (SAS) AF: 0.477 AC: 2304 AN: 4826

European-Finnish (FIN) AF: 0.614 AC: 6502 AN: 10598

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.583 AC: 39630 AN: 67964

Other (OTH) AF: 0.510 AC: 1078 AN: 2114

Alfa AF: 0.557 Hom.: 34992

Bravo AF: 0.505

TwinsUK AF: 0.585 AC: 2169

ALSPAC AF: 0.581 AC: 2238

ESP6500AA AF: 0.461 AC: 2015

ESP6500EA AF: 0.567 AC: 4847

ExAC AF: 0.406 AC: 44699

Asia WGS AF: 0.415 AC: 1447 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	0.10
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.9
DANN	Benign	0.94
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.047
Sift	Benign	0.23	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.065
MutPred		0.052		Gain of MoRF binding (P = 0.0155)
MPC		0.019
ClinPred		0.0052	T
GERP RS		-0.47
Varity_R		0.068
gMVP		0.21
Mutation Taster		=99/1	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: rs12900805; hg19: chr15-90174824; COSMIC: COSV51544331; COSMIC: COSV51544331;