Genetic Variant NM_001546.4:c.208G>A (chr6-19837962-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_001546.4(ID4):c.208G>A(p.Asp70Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000495 in 1,413,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

ID4
NM_001546.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.16

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID4	NM_001546.4 link	c.208G>A	p.Asp70Asn	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.208G>A	p.Asp70Asn	missense_variant	Exon 1 of 3	1	NM_001546.4	ENSP00000367972.3		P47928
LNC-LBCS	ENST00000432171.2 link	n.263+856C>T		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

194574

AF XY:

0.00

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:

0.00000495

AC:

AN:

1413126

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

700718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30600

American (AMR)

AF:

0.00

AC:

AN:

38634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24698

East Asian (EAS)

AF:

0.00

AC:

AN:

35912

South Asian (SAS)

AF:

0.00

AC:

AN:

80116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000643

AC:

AN:

1088356

Other (OTH)

AF:

0.00

AC:

AN:

58360

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.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.208G>A (p.D70N) alteration is located in exon 1 (coding exon 1) of the ID4 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the aspartic acid (D) at amino acid position 70 to be replaced by an asparagine (N). 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

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.75

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.7

PhyloP100

7.2

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.60

Sift

Benign

0.12

Sift4G

Benign

0.24

Polyphen

1.0

Vest4

0.51

MutPred

0.30

Gain of MoRF binding (P = 0.054);

MVP

1.0

MPC

1.6

ClinPred

0.98

GERP RS

2.9

Varity_R

0.50

gMVP

0.58

Mutation Taster

=74/26

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.208G>A

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