Genetic Variant ID4:p.Pro147Gln (chr6-19838194-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001546.4(ID4):c.440C>A(p.Pro147Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000164 in 1,222,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

ID4
NM_001546.4 missense, splice_region

Scores

Splicing: ADA: 0.1570

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.850

Publications

0 publications found

Variant links:

Genes affected

ID4 (HGNC:5363): (inhibitor of DNA binding 4) This gene encodes a member of the inhibitor of DNA binding (ID) protein family. The encoded protein lacks DNA binding ability, and instead regulates gene expression through binding to and inhibiting basic helix-loop-helix transcription factors. This protein has been implicated in the regulation of diverse cellular processes that play a role in development and tumorigenesis. [provided by RefSeq, Aug 2017]

ID4 links:

LNC-LBCS (HGNC:54418): (lncRNA bladder and prostate cancer suppressor, hnRNPK interacting)

LNC-LBCS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID4	NM_001546.4 link	c.440C>A	p.Pro147Gln	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000378700.8	NP_001537.1	P47928

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ID4	ENST00000378700.8 link	c.440C>A	p.Pro147Gln	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_001546.4	ENSP00000367972.3		P47928
LNC-LBCS	ENST00000432171.2 link	n.263+624G>T		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000164

AC:

AN:

1222666

Hom.:

Cov.:

AF XY:

0.00000336

AC XY:

AN XY:

596040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23928

American (AMR)

AF:

0.00

AC:

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16726

East Asian (EAS)

AF:

0.00

AC:

AN:

27184

South Asian (SAS)

AF:

0.0000196

AC:

AN:

51122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4376

European-Non Finnish (NFE)

AF:

9.99e-7

AC:

AN:

1001048

Other (OTH)

AF:

0.00

AC:

AN:

49878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 10, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.440C>A (p.P147Q) alteration is located in exon 1 (coding exon 1) of the ID4 gene. This alteration results from a C to A substitution at nucleotide position 440, causing the proline (P) at amino acid position 147 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.0027

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

0.044

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.2

PhyloP100

0.85

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.32

REVEL

Uncertain

0.30

Sift

Benign

0.068

Sift4G

Benign

0.56

Polyphen

1.0

Vest4

0.15

MutPred

0.12

Loss of glycosylation at T145 (P = 0.063);

MVP

0.92

MPC

1.5

ClinPred

0.77

GERP RS

2.6

Varity_R

0.15

gMVP

0.51

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.16

dbscSNV1_RF

Benign

0.33

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