15-89632939-G-T

Variant names:

• chr15-89632939-G-T
• rs147407072
• NM_198525.3:c.2776C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_198525.3(KIF7):​c.2776C>A​(p.Arg926Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000199 in 1,558,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: KIF7 NM_198525.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.19
• Publications: 2 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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 15-89632939-G-T is Benign according to our data. Variant chr15-89632939-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2776C>A	p.Arg926Arg	synonymous	Exon 14 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.2776C>A	p.Arg926Arg	synonymous	Exon 14 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2899C>A	p.Arg967Arg	synonymous	Exon 14 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2788C>A	p.Arg930Arg	synonymous	Exon 14 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.0000282 AC: 4 AN: 141648 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247870 AF XY: 0.0000149

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 27 AN: 1416908 Hom.: 0 Cov.: 54 AF XY: 0.0000213 AC XY: 15 AN XY: 704484

African (AFR) AF: 0.00 AC: 0 AN: 32414

American (AMR) AF: 0.00 AC: 0 AN: 43740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24528

East Asian (EAS) AF: 0.00 AC: 0 AN: 38232

South Asian (SAS) AF: 0.00 AC: 0 AN: 85884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.0000249 AC: 27 AN: 1082308

Other (OTH) AF: 0.00 AC: 0 AN: 57748

GnomAD4 genome AF: 0.0000282 AC: 4 AN: 141648 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 67900

African (AFR) AF: 0.0000784 AC: 3 AN: 38280

American (AMR) AF: 0.00 AC: 0 AN: 13488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 4848

South Asian (SAS) AF: 0.00 AC: 0 AN: 4502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65958

Other (OTH) AF: 0.00 AC: 0 AN: 1962

Alfa AF: 0.0000558 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs147407072; hg19: chr15-90176170;