6-19838119-C-G

Variant names:

• chr6-19838119-C-G
• rs769162564
• NM_001546.4:c.365C>G

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.365C>G​(p.Ala122Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,585,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ID4 NM_001546.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71
• 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=0.1149402).
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ID4	NM_001546.4	c.365C>G	p.Ala122Gly	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.365C>G	p.Ala122Gly	missense_variant	Exon 1 of 3	1	NM_001546.4	ENSP00000367972.3
LNC-LBCS	ENST00000432171.2	n.263+699G>C		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151928 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 33 AN: 202148 AF XY: 0.000108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000482

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.000403

GnomAD4 exome AF: 0.000131 AC: 188 AN: 1432990 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 87 AN XY: 711654

African (AFR) AF: 0.00 AC: 0 AN: 32118

American (AMR) AF: 0.000656 AC: 27 AN: 41142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37826

South Asian (SAS) AF: 0.00 AC: 0 AN: 82630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.000136 AC: 150 AN: 1099190

Other (OTH) AF: 0.000186 AC: 11 AN: 59144

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74330

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.000458 AC: 7 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.000103 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.365C>G (p.A122G) alteration is located in exon 1 (coding exon 1) of the ID4 gene. This alteration results from a C to G substitution at nucleotide position 365, causing the alanine (A) at amino acid position 122 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	0.089
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.35
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.26
Sift	Benign	0.29	T
Sift4G	Benign	0.48	T
Polyphen		0.030	B
Vest4		0.14
MVP		0.94
MPC		0.64
ClinPred		0.019	T
GERP RS		1.7
Varity_R		0.077
gMVP		0.51
Mutation Taster		=83/17	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: rs769162564; hg19: chr6-19838350;