rs557291472

Variant names:

• chr6-19837926-G-A
• rs557291472
• NM_001546.4:c.172G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-19837926-G-A
• chr6-19837926-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001546.4(ID4):​c.172G>A​(p.Asp58Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,436,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: ID4 NM_001546.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3507586).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID4	NM_001546.4	c.172G>A	p.Asp58Asn	missense_variant	Exon 1 of 3	ENST00000378700.8	NP_001537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ID4	ENST00000378700.8	c.172G>A	p.Asp58Asn	missense_variant	Exon 1 of 3	1	NM_001546.4	ENSP00000367972.3
LNC-LBCS	ENST00000432171.2	n.263+892C>T		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151300 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.0000282 AC: 3 AN: 106360 AF XY: 0.0000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000199

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: 0.00000389 AC: 5 AN: 1285668 Hom.: 0 Cov.: 32 AF XY: 0.00000474 AC XY: 3 AN XY: 632574

African (AFR) AF: 0.00 AC: 0 AN: 26756

American (AMR) AF: 0.000159 AC: 4 AN: 25212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21678

East Asian (EAS) AF: 0.0000358 AC: 1 AN: 27934

South Asian (SAS) AF: 0.00 AC: 0 AN: 62964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1019082

Other (OTH) AF: 0.00 AC: 0 AN: 52124

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151300 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73870

African (AFR) AF: 0.00 AC: 0 AN: 41360

American (AMR) AF: 0.0000658 AC: 1 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67736

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172G>A (p.D58N) 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 172, causing the aspartic acid (D) at amino acid position 58 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	Benign	0.21
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		3.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.24
Sift	Benign	0.036	D
Sift4G	Benign	0.080	T
Polyphen		0.58	P
Vest4		0.19
MutPred		0.44		Gain of catalytic residue at D58 (P = 0.0054);
MVP		0.99
MPC		0.70
ClinPred		0.27	T
GERP RS		2.2
Varity_R		0.14
gMVP		0.28
Mutation Taster		=79/21	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: rs557291472; hg19: chr6-19838157; COSMIC: COSV66343143;