1-23558974-T-C

Variant names:

• chr1-23558974-T-C
• rs369324511
• NM_002167.5:c.346A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002167.5(ID3):​c.346A>G​(p.Ser116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ID3 NM_002167.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

Genes affected

ID3 (HGNC:5362): (inhibitor of DNA binding 3) The protein encoded by this gene is a helix-loop-helix (HLH) protein that can form heterodimers with other HLH proteins. However, the encoded protein lacks a basic DNA-binding domain and therefore inhibits the DNA binding of any HLH protein with which it interacts. [provided by RefSeq, Aug 2011]

ENSG00000307540 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.068573296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID3	NM_002167.5	c.346A>G	p.Ser116Gly	missense_variant	Exon 2 of 3	ENST00000374561.6	NP_002158.3
LOC124903876	XR_007065537.1	n.282+6879T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ID3	ENST00000374561.6	c.346A>G	p.Ser116Gly	missense_variant	Exon 2 of 3	1	NM_002167.5	ENSP00000363689.5
ID3	ENST00000486541.1	n.363A>G		non_coding_transcript_exon_variant	Exon 2 of 2	1
ID3	ENST00000463312.1	n.102A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000307540	ENST00000826972.1	n.204-13773T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251232 AF XY: 0.00

Gnomad AFR exome AF: 0.000123

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: 0.00000205 AC: 3 AN: 1461800 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727210

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.0000724 AC: 3 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346A>G (p.S116G) alteration is located in exon 2 (coding exon 2) of the ID3 gene. This alteration results from a A to G substitution at nucleotide position 346, causing the serine (S) at amino acid position 116 to be replaced by a glycine (G). 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	0.065
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.11
Sift	Benign	0.070	T
Sift4G	Benign	0.45	T
Polyphen		0.17	B
Vest4		0.24
MVP		0.42
MPC		0.13
ClinPred		0.041	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.29
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369324511; hg19: chr1-23885465;