chr17-2057159-C-T

Position:

• chr17-2057159-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006497.4(HIC1):​c.469C>T​(p.Arg157Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0350

Genes affected

HIC1 (HGNC:4909): (HIC ZBTB transcriptional repressor 1) This gene functions as a growth regulatory and tumor repressor gene. Hypermethylation or deletion of the region of this gene have been associated with tumors and the contiguous-gene syndrome, Miller-Dieker syndrome. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122427285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIC1	NM_006497.4	c.469C>T	p.Arg157Trp	missense_variant	2/2	ENST00000619757.5
HIC1	NM_001098202.1	c.526C>T	p.Arg176Trp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIC1	ENST00000619757.5	c.469C>T	p.Arg157Trp	missense_variant	2/2	1	NM_006497.4	P4
HIC1	ENST00000399849.4	c.469C>T	p.Arg157Trp	missense_variant	2/2	1		P4
HIC1	ENST00000322941.3	c.526C>T	p.Arg176Trp	missense_variant	2/2	5		A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1169474 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 569168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.526C>T (p.R176W) alteration is located in exon 2 (coding exon 2) of the HIC1 gene. This alteration results from a C to T substitution at nucleotide position 526, causing the arginine (R) at amino acid position 176 to be replaced by a tryptophan (W). 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	0.59
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	.;.;D
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	0.72	N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Benign	0.026
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.078	.;.;B
Vest4		0.16
MutPred		0.36		.;.;Loss of methylation at R176 (P = 0.0068);
MVP		0.16
ClinPred		0.60	D
GERP RS		0.57
Varity_R		0.16
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1960453;