rs72750755

Variant names:

• chr15-89645161-A-T
• rs72750755
• NM_198525.3:c.2043T>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_198525.3(KIF7):​c.2043T>A​(p.Val681Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,604,452 control chromosomes in the GnomAD database, including 1,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (86 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1361 hom.)
• Consequence: KIF7 NM_198525.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.294
• Publications: 9 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 -16 ACMG points.

• BP6: Variant 15-89645161-A-T is Benign according to our data. Variant chr15-89645161-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0515 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.2043T>A	p.Val681Val	synonymous	Exon 10 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.2043T>A	p.Val681Val	synonymous	Exon 10 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2166T>A	p.Val722Val	synonymous	Exon 10 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2055T>A	p.Val685Val	synonymous	Exon 10 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4466 AN: 152176 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0566

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0350 AC: 8516 AN: 243136 AF XY: 0.0381

Gnomad AFR exome AF: 0.00609

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.0363

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0399 AC: 57934 AN: 1452158 Hom.: 1361 Cov.: 33 AF XY: 0.0409 AC XY: 29576 AN XY: 722876

African (AFR) AF: 0.00624 AC: 209 AN: 33480

American (AMR) AF: 0.0191 AC: 856 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 793 AN: 26126

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39698

South Asian (SAS) AF: 0.0635 AC: 5477 AN: 86258

European-Finnish (FIN) AF: 0.0398 AC: 1747 AN: 43866

Middle Eastern (MID) AF: 0.0526 AC: 303 AN: 5758

European-Non Finnish (NFE) AF: 0.0417 AC: 46375 AN: 1111934

Other (OTH) AF: 0.0359 AC: 2167 AN: 60326

GnomAD4 genome AF: 0.0293 AC: 4467 AN: 152294 Hom.: 86 Cov.: 32 AF XY: 0.0292 AC XY: 2172 AN XY: 74472

African (AFR) AF: 0.00698 AC: 290 AN: 41574

American (AMR) AF: 0.0295 AC: 452 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0570 AC: 275 AN: 4822

European-Finnish (FIN) AF: 0.0269 AC: 286 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0434 AC: 2954 AN: 68012

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0382 Hom.: 23

Bravo AF: 0.0269

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0462

EpiControl AF: 0.0429

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Acrocallosal syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72750755; hg19: chr15-90188392;