rs61741227

Variant names:

• chr15-89631594-G-A
• rs61741227
• NM_198525.3:c.3012C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198525.3(KIF7):​c.3012C>T​(p.Arg1004Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,563,000 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (17 hom., cov: 34)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: KIF7 NM_198525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.34
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-89631594-G-A is Benign according to our data. Variant chr15-89631594-G-A is described in ClinVar as Benign. ClinVar VariationId is 129414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00777 (1183/152296) while in subpopulation AFR AF = 0.0269 (1117/41570). AF 95% confidence interval is 0.0256. There are 17 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.3012C>T	p.Arg1004Arg	synonymous	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.3012C>T	p.Arg1004Arg	synonymous	Exon 15 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.3135C>T	p.Arg1045Arg	synonymous	Exon 15 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.3024C>T	p.Arg1008Arg	synonymous	Exon 15 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152178 Hom.: 17 Cov.: 34

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00192 AC: 331 AN: 172230 AF XY: 0.00149

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000228

Gnomad EAS exome AF: 0.000155

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.000791 AC: 1116 AN: 1410704 Hom.: 15 Cov.: 38 AF XY: 0.000759 AC XY: 529 AN XY: 697206

African (AFR) AF: 0.0257 AC: 825 AN: 32078

American (AMR) AF: 0.00157 AC: 60 AN: 38308

Ashkenazi Jewish (ASJ) AF: 0.000512 AC: 13 AN: 25378

East Asian (EAS) AF: 0.00 AC: 0 AN: 36744

South Asian (SAS) AF: 0.0000870 AC: 7 AN: 80418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49038

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5686

European-Non Finnish (NFE) AF: 0.0000544 AC: 59 AN: 1084706

Other (OTH) AF: 0.00240 AC: 140 AN: 58348

GnomAD4 genome AF: 0.00777 AC: 1183 AN: 152296 Hom.: 17 Cov.: 34 AF XY: 0.00748 AC XY: 557 AN XY: 74460

African (AFR) AF: 0.0269 AC: 1117 AN: 41570

American (AMR) AF: 0.00301 AC: 46 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00409 Hom.: 3

Bravo AF: 0.00855

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.10
DANN	Benign	0.92
PhyloP100		-2.3
Mutation Taster		=100/0	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: rs61741227; hg19: chr15-90174825;