rs8037349

Variant names:

• chr15-89648596-T-C
• rs8037349
• NM_198525.3:c.1102A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-89648596-T-C
• chr15-89648596-T-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.1102A>G​(p.Thr368Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.901 in 1,528,112 control chromosomes in the GnomAD database, including 622,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61568 hom., cov: 33)
  • Exomes 𝑓: 0.90 (560552 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0580
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.2696605E-7).
• BP6: Variant 15-89648596-T-C is Benign according to our data. Variant chr15-89648596-T-C is described in ClinVar as Benign. ClinVar VariationId is 96649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 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.1102A>G	p.Thr368Ala	missense	Exon 5 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.1102A>G	p.Thr368Ala	missense	Exon 5 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000445906.1	TSL:1	n.*761A>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000395906.1	F8WD21
	KIF7	ENST00000445906.1	TSL:1	n.*761A>G		3_prime_UTR	Exon 5 of 5	ENSP00000395906.1	F8WD21

Frequencies

GnomAD3 genomes AF: 0.902 AC: 135810 AN: 150546 Hom.: 61530 Cov.: 33

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.950

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.878

Gnomad MID AF: 0.901

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.897

GnomAD2 exomes AF: 0.855 AC: 111890 AN: 130850 AF XY: 0.861

Gnomad AFR exome AF: 0.966

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.841

Gnomad EAS exome AF: 0.743

Gnomad FIN exome AF: 0.874

Gnomad NFE exome AF: 0.914

Gnomad OTH exome AF: 0.867

GnomAD4 exome AF: 0.901 AC: 1240843 AN: 1377476 Hom.: 560552 Cov.: 43 AF XY: 0.901 AC XY: 612086 AN XY: 679702

African (AFR) AF: 0.963 AC: 30082 AN: 31248

American (AMR) AF: 0.745 AC: 26345 AN: 35376

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 21048 AN: 24830

East Asian (EAS) AF: 0.698 AC: 24619 AN: 35268

South Asian (SAS) AF: 0.876 AC: 69266 AN: 79030

European-Finnish (FIN) AF: 0.880 AC: 30084 AN: 34176

Middle Eastern (MID) AF: 0.877 AC: 4887 AN: 5570

European-Non Finnish (NFE) AF: 0.915 AC: 983153 AN: 1074626

Other (OTH) AF: 0.896 AC: 51359 AN: 57352

GnomAD4 genome AF: 0.902 AC: 135891 AN: 150636 Hom.: 61568 Cov.: 33 AF XY: 0.897 AC XY: 66042 AN XY: 73608

African (AFR) AF: 0.960 AC: 39696 AN: 41352

American (AMR) AF: 0.797 AC: 12061 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 2891 AN: 3464

East Asian (EAS) AF: 0.741 AC: 3796 AN: 5126

South Asian (SAS) AF: 0.853 AC: 4119 AN: 4830

European-Finnish (FIN) AF: 0.878 AC: 8678 AN: 9888

Middle Eastern (MID) AF: 0.893 AC: 259 AN: 290

European-Non Finnish (NFE) AF: 0.913 AC: 61649 AN: 67532

Other (OTH) AF: 0.893 AC: 1876 AN: 2100

Alfa AF: 0.907 Hom.: 13632

Bravo AF: 0.896

TwinsUK AF: 0.912 AC: 3383

ALSPAC AF: 0.917 AC: 3533

ESP6500AA AF: 0.966 AC: 1327

ESP6500EA AF: 0.904 AC: 2869

ExAC AF: 0.879 AC: 14612

Asia WGS AF: 0.794 AC: 2753 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Acrocallosal syndrome (3)
-	-	2	not provided (2)
-	-	1	Hydrolethalus syndrome 2 (1)
-	-	1	KIF7-related disorder (1)
-	-	1	Multiple epiphyseal dysplasia, Al-Gazali type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.3
DANN	Benign	0.41
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.12	N
PhyloP100		-0.058
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.061
Sift	Benign	0.46	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.018
ClinPred		0.0015	T
GERP RS		1.9
Varity_R		0.025
gMVP		0.25
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: rs8037349; hg19: chr15-90191827; COSMIC: COSV67997604;