17-2057193-C-A

Position:

• chr17-2057193-C-A

Variant summary

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

The NM_006497.4(HIC1):​c.503C>A​(p.Ala168Asp) 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: 3.45

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=0.1032514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIC1	NM_006497.4	c.503C>A	p.Ala168Asp	missense_variant	2/2	ENST00000619757.5
HIC1	NM_001098202.1	c.560C>A	p.Ala187Asp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIC1	ENST00000619757.5	c.503C>A	p.Ala168Asp	missense_variant	2/2	1	NM_006497.4	P4
HIC1	ENST00000399849.4	c.503C>A	p.Ala168Asp	missense_variant	2/2	1		P4
HIC1	ENST00000322941.3	c.560C>A	p.Ala187Asp	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: 1231738 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 605520

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

Jun 05, 2024

The c.560C>A (p.A187D) alteration is located in exon 2 (coding exon 2) of the HIC1 gene. This alteration results from a C to A substitution at nucleotide position 560, causing the alanine (A) at amino acid position 187 to be replaced by an aspartic acid (D). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	.;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.0	N;.;N
REVEL	Benign	0.027
Sift	Benign	0.065	T;.;D
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0030	.;.;B
Vest4		0.12
MutPred		0.20		.;.;Gain of relative solvent accessibility (P = 0.0082);
MVP		0.13
ClinPred		0.55	D
GERP RS		1.1
Varity_R		0.34
gMVP		0.62

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: chr17-1960487;