17-2057154-C-T

Variant names:

• chr17-2057154-C-T
• NM_006497.4:c.464C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006497.4(HIC1):​c.464C>T​(p.Pro155Leu) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • 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: 0.691

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061178356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIC1	NM_006497.4	c.464C>T	p.Pro155Leu	missense_variant	Exon 2 of 2	ENST00000619757.5	NP_006488.2
HIC1	NM_001098202.1	c.521C>T	p.Pro174Leu	missense_variant	Exon 2 of 2		NP_001091672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIC1	ENST00000619757.5	c.464C>T	p.Pro155Leu	missense_variant	Exon 2 of 2	1	NM_006497.4	ENSP00000477858.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1158494 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 562286

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.521C>T (p.P174L) 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 521, causing the proline (P) at amino acid position 174 to be replaced by a leucine (L). 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	0.32
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.20	.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.65	T;.;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.040
Sift	Benign	0.44	T;.;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.10
MutPred		0.24		.;.;Loss of relative solvent accessibility (P = 0.0186);
MVP		0.14
ClinPred		0.089	T
GERP RS		2.6
Varity_R		0.057
gMVP		0.27

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: chr17-1960448;