chr17-2057489-C-G

Position:

• chr17-2057489-C-G

Variant summary

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

The NM_006497.4(HIC1):​c.799C>G​(p.Leu267Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,332,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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=0.18347621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIC1	NM_006497.4	c.799C>G	p.Leu267Val	missense_variant	2/2	ENST00000619757.5
HIC1	NM_001098202.1	c.856C>G	p.Leu286Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIC1	ENST00000619757.5	c.799C>G	p.Leu267Val	missense_variant	2/2	1	NM_006497.4	P4
HIC1	ENST00000399849.4	c.799C>G	p.Leu267Val	missense_variant	2/2	1		P4
HIC1	ENST00000322941.3	c.856C>G	p.Leu286Val	missense_variant	2/2	5		A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1332294 Hom.: 0 Cov.: 32 AF XY: 0.00000152 AC XY: 1 AN XY: 656800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000333

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

Bravo AF: 0.00000756

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

Dec 26, 2023

The c.856C>G (p.L286V) alteration is located in exon 2 (coding exon 2) of the HIC1 gene. This alteration results from a C to G substitution at nucleotide position 856, causing the leucine (L) at amino acid position 286 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	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.3
DANN	Benign	0.94
DEOGEN2	Benign	0.15	.;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.54	T;.;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.39	N;.;N
REVEL	Benign	0.026
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.46	.;.;P
Vest4		0.17
MutPred		0.20		.;.;Loss of glycosylation at P287 (P = 0.1103);
MVP		0.18
ClinPred		0.030	T
GERP RS		1.9
Varity_R		0.036
gMVP		0.080

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: rs1290656347; hg19: chr17-1960783;