chr6-19837888-C-T

Variant names:

• chr6-19837888-C-T
• rs775900142
• NM_001546.4:c.134C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001546.4(ID4):​c.134C>T​(p.Ala45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,306,528 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: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ID4 NM_001546.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11819938).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID4	NM_001546.4	c.134C>T	p.Ala45Val	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.134C>T	p.Ala45Val	missense_variant	Exon 1 of 3	1	NM_001546.4	ENSP00000367972.3
LNC-LBCS	ENST00000432171.2	n.263+930G>A		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0000333 AC: 5 AN: 149968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000743

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 25024 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: 0.0000138 AC: 16 AN: 1156560 Hom.: 0 Cov.: 32 AF XY: 0.0000160 AC XY: 9 AN XY: 560826

African (AFR) AF: 0.00 AC: 0 AN: 22586

American (AMR) AF: 0.00 AC: 0 AN: 8564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14854

East Asian (EAS) AF: 0.0000394 AC: 1 AN: 25364

South Asian (SAS) AF: 0.0000271 AC: 1 AN: 36926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3422

European-Non Finnish (NFE) AF: 0.0000135 AC: 13 AN: 961296

Other (OTH) AF: 0.0000218 AC: 1 AN: 45902

GnomAD4 genome AF: 0.0000333 AC: 5 AN: 149968 Hom.: 0 Cov.: 32 AF XY: 0.0000410 AC XY: 3 AN XY: 73174

African (AFR) AF: 0.00 AC: 0 AN: 41156

American (AMR) AF: 0.00 AC: 0 AN: 15044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000743 AC: 5 AN: 67336

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000252 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134C>T (p.A45V) alteration is located in exon 1 (coding exon 1) of the ID4 gene. This alteration results from a C to T substitution at nucleotide position 134, causing the alanine (A) at amino acid position 45 to be replaced by a valine (V). 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	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.61	N
REVEL	Benign	0.13
Sift	Benign	0.95	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.33		Loss of methylation at R49 (P = 0.109);
MVP		0.85
MPC		0.62
ClinPred		0.14	T
GERP RS		-0.21
Varity_R		0.056
gMVP		0.40
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs775900142; hg19: chr6-19838119;