dbSNP rs1210076297: HIC1:p.Pro105Thr (chr17-2057003-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006497.4(HIC1):c.313C>A(p.Pro105Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P105S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

HIC1
NM_006497.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.52

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.313C>A	p.Pro105Thr	missense	Exon 2 of 2	NP_006488.2	Q14526-2
	HIC1	NM_001098202.1		c.370C>A	p.Pro124Thr	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.313C>A	p.Pro105Thr	missense	Exon 2 of 2	ENSP00000477858.1	Q14526-2
HIC1	ENST00000399849.4	TSL:1	c.313C>A	p.Pro105Thr	missense	Exon 2 of 2	ENSP00000382742.2	Q14526-2
HIC1	ENST00000322941.3	TSL:5	c.370C>A	p.Pro124Thr	missense	Exon 2 of 2	ENSP00000314080.3	Q14526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370378

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

677838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27820

American (AMR)

AF:

0.00

AC:

AN:

29588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23482

East Asian (EAS)

AF:

0.00

AC:

AN:

32366

South Asian (SAS)

AF:

0.00

AC:

AN:

75510

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5432

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1071998

Other (OTH)

AF:

0.00

AC:

AN:

56332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.75

PhyloP100

3.5

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.40

Sift

Uncertain

0.011

Sift4G

Uncertain

0.038

Polyphen

1.0

Vest4

0.40

MutPred

0.69

Loss of disorder (P = 0.0892)

MVP

0.59

ClinPred

0.98

GERP RS

4.2

Varity_R

0.46

gMVP

0.60

Mutation Taster

=70/30

polymorphism

(source)

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