Genetic Variant NM_001546.4:c.100A>T (chr6-19837854-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001546.4(ID4):c.100A>T(p.Ser34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,073,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

ID4
NM_001546.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26096517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID4	NM_001546.4 link	c.100A>T	p.Ser34Cys	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.100A>T	p.Ser34Cys	missense_variant	Exon 1 of 3	1	NM_001546.4	ENSP00000367972.3		P47928
LNC-LBCS	ENST00000432171.2 link	n.263+964T>A		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000186

AC:

AN:

1073992

Hom.:

Cov.:

AF XY:

0.00000195

AC XY:

AN XY:

513664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21032

American (AMR)

AF:

0.00

AC:

AN:

6750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12118

East Asian (EAS)

AF:

0.00

AC:

AN:

21836

South Asian (SAS)

AF:

0.00

AC:

AN:

24782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2776

European-Non Finnish (NFE)

AF:

0.00000219

AC:

AN:

914384

Other (OTH)

AF:

0.00

AC:

AN:

41354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

Feb 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.100A>T (p.S34C) alteration is located in exon 1 (coding exon 1) of the ID4 gene. This alteration results from a A to T substitution at nucleotide position 100, causing the serine (S) at amino acid position 34 to be replaced by a cysteine (C). 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

0.091

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.26

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

2.2

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.95

REVEL

Benign

0.17

Sift

Benign

0.042

Sift4G

Uncertain

0.0090

Polyphen

0.70

Vest4

0.11

MutPred

0.23

Loss of glycosylation at S34 (P = 0.0062);

MVP

0.89

MPC

1.3

ClinPred

0.51

GERP RS

2.9

PromoterAI

-0.0053

Neutral

(source)

Varity_R

0.13

gMVP

0.56

Mutation Taster

=85/15

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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NM_001546.4:c.100A>T

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