17-2057696-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006497.4(HIC1):c.1006C>T(p.Arg336Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,332,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000038 (0 hom.)
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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 2 ACMG points.

• PM1: In a mutagenesis_site Impairs K-333 acetylation; no effect on sumoylation. Decreases interaction with MTA1. (size 0) in uniprot entity HIC1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19807121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIC1	NM_006497.4	c.1006C>T	p.Arg336Cys	missense_variant	2/2	ENST00000619757.5
HIC1	NM_001098202.1	c.1063C>T	p.Arg355Cys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIC1	ENST00000619757.5	c.1006C>T	p.Arg336Cys	missense_variant	2/2	1	NM_006497.4	P4
HIC1	ENST00000399849.4	c.1006C>T	p.Arg336Cys	missense_variant	2/2	1		P4
HIC1	ENST00000322941.3	c.1063C>T	p.Arg355Cys	missense_variant	2/2	5		A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000228 AC: 2 AN: 87578 Hom.: 0 AF XY: 0.0000398 AC XY: 2 AN XY: 50292

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 SAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000304

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000375 AC: 5 AN: 1332912 Hom.: 0 Cov.: 33 AF XY: 0.00000304 AC XY: 2 AN XY: 658366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000349

Gnomad4 SAS exome AF: 0.0000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000284

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

Jan 02, 2024

The c.1063C>T (p.R355C) 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 1063, causing the arginine (R) at amino acid position 355 to be replaced by a cysteine (C). 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	0.25
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.76	T;.;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.91	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.10
Sift	Uncertain	0.011	D;.;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.96	.;.;D
Vest4		0.36
MutPred		0.17		.;.;Loss of solvent accessibility (P = 0.1434);
MVP		0.35
ClinPred		0.24	T
GERP RS		2.7
Varity_R		0.14
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs756871471; hg19: chr17-1960990;