17-2057556-G-A

Position:

• chr17-2057556-G-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.866G>A​(p.Arg289His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000742 in 1,348,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R289L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.275

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=0.16251078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIC1	NM_006497.4	c.866G>A	p.Arg289His	missense_variant	2/2	ENST00000619757.5
HIC1	NM_001098202.1	c.923G>A	p.Arg308His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIC1	ENST00000619757.5	c.866G>A	p.Arg289His	missense_variant	2/2	1	NM_006497.4	P4
HIC1	ENST00000399849.4	c.866G>A	p.Arg289His	missense_variant	2/2	1		P4
HIC1	ENST00000322941.3	c.923G>A	p.Arg308His	missense_variant	2/2	5		A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.42e-7 AC: 1 AN: 1348330 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 665066

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: 9.41e-7

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

Aug 16, 2021

The c.923G>A (p.R308H) alteration is located in exon 2 (coding exon 2) of the HIC1 gene. This alteration results from a G to A substitution at nucleotide position 923, causing the arginine (R) at amino acid position 308 to be replaced by a histidine (H). 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	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.49	N;.;N
REVEL	Benign	0.081
Sift	Benign	0.16	T;.;T
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.086
MutPred		0.18		.;.;Gain of glycosylation at S304 (P = 0.0627);
MVP		0.31
ClinPred		0.12	T
GERP RS		2.2
Varity_R		0.073
gMVP		0.26

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: rs978348590; hg19: chr17-1960850;