rs755938967

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_152558.5(IQCE):c.395-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000142 in 1,409,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

IQCE
NM_152558.5 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.39

Publications

3 publications found

Variant links:

Genes affected

IQCE (HGNC:29171): (IQ motif containing E) Involved in limb morphogenesis. Predicted to be extrinsic component of membrane. Predicted to be part of plasma membrane protein complex. [provided by Alliance of Genome Resources, Apr 2022]

IQCE Gene-Disease associations (from GenCC):

postaxial polydactyly type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
polydactyly, postaxial, type a7
Inheritance: AR Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

IQCE links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_152558.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of 1, new splice context is: tttgtttatgtttctctaAGtca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 7-2573417-G-A is Pathogenic according to our data. Variant chr7-2573417-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 437834.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152558.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IQCE	NM_152558.5	MANE Select	c.395-1G>A	splice_acceptor intron	N/A	NP_689771.3
IQCE	NM_001287499.2		c.395-1G>A	splice_acceptor intron	N/A	NP_001274428.1	A0A087WX45
IQCE	NM_001287500.2		c.347-1G>A	splice_acceptor intron	N/A	NP_001274429.1	A0A087WX19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IQCE	ENST00000402050.7	TSL:1 MANE Select	c.395-1G>A	splice_acceptor intron	N/A	ENSP00000385597.2	Q6IPM2-1
IQCE	ENST00000623361.3	TSL:1	c.200-1G>A	splice_acceptor intron	N/A	ENSP00000485601.1	Q6IPM2-2
IQCE	ENST00000325997.13	TSL:1	n.*172-1G>A	splice_acceptor intron	N/A	ENSP00000314011.10	X5D7Y5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

243892

AF XY:

0.00000755

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000143

AC:

AN:

1257780

Hom.:

Cov.:

AF XY:

0.0000189

AC XY:

AN XY:

636248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29390

American (AMR)

AF:

0.00

AC:

AN:

43098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25000

East Asian (EAS)

AF:

0.00

AC:

AN:

38868

South Asian (SAS)

AF:

0.000223

AC:

AN:

80806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5436

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

928116

Other (OTH)

AF:

0.00

AC:

AN:

53856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Polydactyly, postaxial, type a7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

PhyloP100

6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.94

Position offset: 1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over