rs112333674

Variant names:

• chr15-89647716-T-C
• rs112333674
• NM_198525.3:c.1444-4A>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.1444-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,559,788 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (111 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (109 hom.)
• Consequence: KIF7 NM_198525.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003085
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.11
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-89647716-T-C is Benign according to our data. Variant chr15-89647716-T-C is described in ClinVar as Benign. ClinVar VariationId is 129405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0683 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.1444-4A>G		splice_region intron	N/A	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.1444-4A>G		splice_region intron	N/A	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.1567-4A>G		splice_region intron	N/A	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.1459-4A>G		splice_region intron	N/A	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3081 AN: 152052 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0705

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00512 AC: 865 AN: 168812 AF XY: 0.00380

Gnomad AFR exome AF: 0.0785

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00217 AC: 3060 AN: 1407618 Hom.: 109 Cov.: 31 AF XY: 0.00183 AC XY: 1278 AN XY: 696478

African (AFR) AF: 0.0772 AC: 2487 AN: 32210

American (AMR) AF: 0.00313 AC: 119 AN: 37960

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 37022

South Asian (SAS) AF: 0.000223 AC: 18 AN: 80690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43368

Middle Eastern (MID) AF: 0.00508 AC: 29 AN: 5714

European-Non Finnish (NFE) AF: 0.000121 AC: 131 AN: 1086738

Other (OTH) AF: 0.00470 AC: 275 AN: 58558

GnomAD4 genome AF: 0.0203 AC: 3086 AN: 152170 Hom.: 111 Cov.: 32 AF XY: 0.0191 AC XY: 1422 AN XY: 74414

African (AFR) AF: 0.0704 AC: 2922 AN: 41506

American (AMR) AF: 0.00712 AC: 109 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67994

Other (OTH) AF: 0.0138 AC: 29 AN: 2106

Alfa AF: 0.0158 Hom.: 32

Bravo AF: 0.0233

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Acrocallosal syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.061
DANN	Benign	0.60
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs112333674; hg19: chr15-90190947;