17-2057495-T-C

Position:

• chr17-2057495-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006497.4(HIC1):​c.805T>C​(p.Ser269Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,333,420 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.541

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042311043).
• BP6: Variant 17-2057495-T-C is Benign according to our data. Variant chr17-2057495-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3105779.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIC1	NM_006497.4	c.805T>C	p.Ser269Pro	missense_variant	2/2	ENST00000619757.5
HIC1	NM_001098202.1	c.862T>C	p.Ser288Pro	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIC1	ENST00000619757.5	c.805T>C	p.Ser269Pro	missense_variant	2/2	1	NM_006497.4	P4
HIC1	ENST00000399849.4	c.805T>C	p.Ser269Pro	missense_variant	2/2	1		P4
HIC1	ENST00000322941.3	c.862T>C	p.Ser288Pro	missense_variant	2/2	5		A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000120 AC: 16 AN: 1333420 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 9 AN XY: 657370

Gnomad4 AFR exome AF: 0.0000373

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: 0.0000133

Gnomad4 OTH exome AF: 0.0000181

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Benign	0.60
DEOGEN2	Benign	0.19	.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.32	T;.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	0.80	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.22	N;.;N
REVEL	Benign	0.037
Sift	Benign	0.53	T;.;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.094
MutPred		0.22		.;.;Loss of phosphorylation at S288 (P = 0.007);
MVP		0.081
ClinPred		0.032	T
GERP RS		2.0
Varity_R		0.047
gMVP		0.036

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: rs2067683318; hg19: chr17-1960789;