rs4646954

Variant names:

• chr10-92574070-G-A
• rs4646954
• NM_004969.4:c.-51C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-92574070-G-A
• chr10-92574070-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004969.4(IDE):​c.-51C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.107 in 1,418,436 control chromosomes in the GnomAD database, including 10,783 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2824 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7959 hom.)
• Consequence: IDE NM_004969.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70
• Publications: 20 publications found

Genes affected

IDE (HGNC:5381): (insulin degrading enzyme) This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]

KIF11 (HGNC:6388): (kinesin family member 11) This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. [provided by RefSeq, Jul 2008]

KIF11 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDE	NM_004969.4	c.-51C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 25	ENST00000265986.11	NP_004960.2
IDE	NM_004969.4	c.-51C>T		5_prime_UTR_variant	Exon 1 of 25	ENST00000265986.11	NP_004960.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDE	ENST00000265986.11	c.-51C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 25	1	NM_004969.4	ENSP00000265986.6
IDE	ENST00000265986.11	c.-51C>T		5_prime_UTR_variant	Exon 1 of 25	1	NM_004969.4	ENSP00000265986.6

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24406 AN: 152126 Hom.: 2812 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0542

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0879

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.131 AC: 12453 AN: 95136 AF XY: 0.127

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.0503

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.0623

Gnomad NFE exome AF: 0.0846

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.100 AC: 127246 AN: 1266192 Hom.: 7959 Cov.: 19 AF XY: 0.102 AC XY: 64109 AN XY: 628302

African (AFR) AF: 0.327 AC: 8467 AN: 25856

American (AMR) AF: 0.220 AC: 5878 AN: 26658

Ashkenazi Jewish (ASJ) AF: 0.0514 AC: 1193 AN: 23206

East Asian (EAS) AF: 0.177 AC: 5389 AN: 30512

South Asian (SAS) AF: 0.172 AC: 12387 AN: 72126

European-Finnish (FIN) AF: 0.0658 AC: 2455 AN: 37298

Middle Eastern (MID) AF: 0.0826 AC: 346 AN: 4188

European-Non Finnish (NFE) AF: 0.0864 AC: 85748 AN: 992810

Other (OTH) AF: 0.101 AC: 5383 AN: 53538

GnomAD4 genome AF: 0.161 AC: 24459 AN: 152244 Hom.: 2824 Cov.: 33 AF XY: 0.159 AC XY: 11835 AN XY: 74456

African (AFR) AF: 0.318 AC: 13193 AN: 41526

American (AMR) AF: 0.178 AC: 2716 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 189 AN: 3470

East Asian (EAS) AF: 0.127 AC: 655 AN: 5174

South Asian (SAS) AF: 0.169 AC: 817 AN: 4828

European-Finnish (FIN) AF: 0.0542 AC: 576 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0879 AC: 5981 AN: 68018

Other (OTH) AF: 0.144 AC: 303 AN: 2108

Alfa AF: 0.0943 Hom.: 955

Bravo AF: 0.176

Asia WGS AF: 0.148 AC: 517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.96
PhyloP100		3.7
PromoterAI		0.010	Neutral
Mutation Taster		=300/0	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: rs4646954; hg19: chr10-94333827; COSMIC: COSV56422778; COSMIC: COSV56422778;