Genetic Variant HIC1:p.Pro171Leu (chr17-2057202-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006497.4(HIC1):c.512C>T(p.Pro171Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P171R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HIC1
NM_006497.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.607

Publications

0 publications found

Variant links:

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]

HIC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13784409).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006497.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIC1	NM_006497.4	MANE Select	c.512C>T	p.Pro171Leu	missense	Exon 2 of 2	NP_006488.2	Q14526-2
	HIC1	NM_001098202.1		c.569C>T	p.Pro190Leu	missense	Exon 2 of 2	NP_001091672.1	Q14526-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HIC1	ENST00000619757.5	TSL:1 MANE Select	c.512C>T	p.Pro171Leu	missense	Exon 2 of 2	ENSP00000477858.1	Q14526-2
HIC1	ENST00000399849.4	TSL:1	c.512C>T	p.Pro171Leu	missense	Exon 2 of 2	ENSP00000382742.2	Q14526-2
HIC1	ENST00000322941.3	TSL:5	c.569C>T	p.Pro190Leu	missense	Exon 2 of 2	ENSP00000314080.3	Q14526-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151530

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1236720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

608262

African (AFR)

AF:

0.00

AC:

AN:

24314

American (AMR)

AF:

0.00

AC:

AN:

16136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18914

East Asian (EAS)

AF:

0.00

AC:

AN:

25990

South Asian (SAS)

AF:

0.00

AC:

AN:

61256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3570

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1005852

Other (OTH)

AF:

0.00

AC:

AN:

50196

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151530

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41362

American (AMR)

AF:

0.0000658

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67818

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.61

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.5

REVEL

Benign

0.016

Sift

Uncertain

0.0080

Sift4G

Benign

0.061

Polyphen

0.029

Vest4

0.13

MutPred

0.21

Loss of glycosylation at P190 (P = 0.0406)

MVP

0.26

ClinPred

0.24

GERP RS

2.5

Varity_R

0.060

gMVP

0.41

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over