NM_198525.3:c.2658A>C

Variant names:

• chr15-89633201-T-G
• rs3803531
• NM_198525.3:c.2658A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198525.3(KIF7):​c.2658A>C​(p.Ala886Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,603,078 control chromosomes in the GnomAD database, including 641,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55566 hom., cov: 32)
  • Exomes 𝑓: 0.90 (585595 hom.)
• Consequence: KIF7 NM_198525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.05
• Publications: 24 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=-0.92).
• BP6: Variant 15-89633201-T-G is Benign according to our data. Variant chr15-89633201-T-G is described in ClinVar as Benign. ClinVar VariationId is 129413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.912 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.2658A>C	p.Ala886Ala	synonymous	Exon 13 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.2658A>C	p.Ala886Ala	synonymous	Exon 13 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2781A>C	p.Ala927Ala	synonymous	Exon 13 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2670A>C	p.Ala890Ala	synonymous	Exon 13 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129491 AN: 152040 Hom.: 55528 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.949

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.918

Gnomad OTH AF: 0.856

GnomAD2 exomes AF: 0.849 AC: 200975 AN: 236596 AF XY: 0.858

Gnomad AFR exome AF: 0.779

Gnomad AMR exome AF: 0.714

Gnomad ASJ exome AF: 0.843

Gnomad EAS exome AF: 0.701

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.916

Gnomad OTH exome AF: 0.868

GnomAD4 exome AF: 0.896 AC: 1300671 AN: 1450920 Hom.: 585595 Cov.: 63 AF XY: 0.897 AC XY: 647197 AN XY: 721534

African (AFR) AF: 0.776 AC: 25875 AN: 33364

American (AMR) AF: 0.723 AC: 31731 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 22037 AN: 25982

East Asian (EAS) AF: 0.669 AC: 26427 AN: 39526

South Asian (SAS) AF: 0.873 AC: 74323 AN: 85146

European-Finnish (FIN) AF: 0.886 AC: 41984 AN: 47404

Middle Eastern (MID) AF: 0.864 AC: 4815 AN: 5576

European-Non Finnish (NFE) AF: 0.919 AC: 1020401 AN: 1109882

Other (OTH) AF: 0.883 AC: 53078 AN: 60122

GnomAD4 genome AF: 0.852 AC: 129582 AN: 152158 Hom.: 55566 Cov.: 32 AF XY: 0.848 AC XY: 63081 AN XY: 74392

African (AFR) AF: 0.782 AC: 32444 AN: 41498

American (AMR) AF: 0.771 AC: 11784 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 2901 AN: 3472

East Asian (EAS) AF: 0.701 AC: 3605 AN: 5142

South Asian (SAS) AF: 0.848 AC: 4095 AN: 4828

European-Finnish (FIN) AF: 0.888 AC: 9429 AN: 10618

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.918 AC: 62409 AN: 68006

Other (OTH) AF: 0.852 AC: 1799 AN: 2112

Alfa AF: 0.883 Hom.: 31875

Bravo AF: 0.836

Asia WGS AF: 0.772 AC: 2687 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
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.25
DANN	Benign	0.42
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs3803531; hg19: chr15-90176432; COSMIC: COSV67997586; COSMIC: COSV67997586;