Genetic Variant NM_152558.5:c.3G>A (chr7-2559184-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_152558.5(IQCE):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IQCE
NM_152558.5 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.79

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 66 codons. Genomic position: 2571591. Lost 0.094 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-2559184-G-A is Pathogenic according to our data. Variant chr7-2559184-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1030264.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCE	NM_152558.5 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 22	ENST00000402050.7	NP_689771.3	Q6IPM2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQCE	ENST00000402050.7 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 22	1	NM_152558.5	ENSP00000385597.2		Q6IPM2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1064276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

502610

African (AFR)

AF:

0.00

AC:

AN:

22184

American (AMR)

AF:

0.00

AC:

AN:

7808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13428

East Asian (EAS)

AF:

0.00

AC:

AN:

25106

South Asian (SAS)

AF:

0.00

AC:

AN:

19448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2878

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

909306

Other (OTH)

AF:

0.00

AC:

AN:

42356

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Polydactyly, postaxial, type a7

Pathogenic:1

Jun 03, 2020

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T;.;T;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D

MetaSVM

Benign

-0.99

PhyloP100

1.8

PROVEAN

Benign

-1.2

N;N;N;.;N;.

REVEL

Benign

0.19

Sift

Uncertain

0.024

D;D;D;.;D;.

Sift4G

Uncertain

0.052

T;D;D;D;D;D

Polyphen

0.075

B;.;B;.;.;.

Vest4

0.84

MutPred

0.83

Gain of catalytic residue at M1 (P = 0.01);Gain of catalytic residue at M1 (P = 0.01);Gain of catalytic residue at M1 (P = 0.01);Gain of catalytic residue at M1 (P = 0.01);Gain of catalytic residue at M1 (P = 0.01);Gain of catalytic residue at M1 (P = 0.01);

MVP

0.38

ClinPred

0.63

GERP RS

3.1

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.45

gMVP

0.062

Mutation Taster

=86/114

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over