Genetic Variant ID4:p.Pro127Arg (chr6-19838134-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001546.4(ID4):c.380C>G(p.Pro127Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000918 in 1,415,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

ID4
NM_001546.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.588

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22269225).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID4	NM_001546.4 link	c.380C>G	p.Pro127Arg	missense_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.380C>G	p.Pro127Arg	missense_variant	Exon 1 of 3	1	NM_001546.4	ENSP00000367972.3		P47928
LNC-LBCS	ENST00000432171.2 link	n.263+684G>C		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000918

AC:

AN:

1415956

Hom.:

Cov.:

AF XY:

0.00000570

AC XY:

AN XY:

701792

show subpopulations

African (AFR)

AF:

0.0000319

AC:

AN:

31352

American (AMR)

AF:

0.0000775

AC:

AN:

38722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24948

East Asian (EAS)

AF:

0.00

AC:

AN:

36626

South Asian (SAS)

AF:

0.00

AC:

AN:

80968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00000459

AC:

AN:

1090014

Other (OTH)

AF:

0.0000684

AC:

AN:

58512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000317

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.380C>G (p.P127R) alteration is located in exon 1 (coding exon 1) of the ID4 gene. This alteration results from a C to G substitution at nucleotide position 380, causing the proline (P) at amino acid position 127 to be replaced by an arginine (R). 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

0.17

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.21

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.22

MetaSVM

Uncertain

-0.0025

MutationAssessor

Benign

0.0

PhyloP100

0.59

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.78

REVEL

Uncertain

0.34

Sift

Benign

0.46

Sift4G

Benign

0.36

Polyphen

0.82

Vest4

0.077

MutPred

0.16

Loss of glycosylation at P127 (P = 0.029);

MVP

0.99

MPC

1.6

ClinPred

0.16

GERP RS

2.6

Varity_R

0.089

gMVP

0.54

Mutation Taster

=84/16

polymorphism

(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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6-19838134-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over