rs769064912

Variant names:

• chr17-2057486-G-A
• rs769064912
• NM_006497.4:c.796G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006497.4(HIC1):​c.796G>A​(p.Ala266Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,483,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A266G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: HIC1 NM_006497.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.13
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013625175).
• BS2: High AC in GnomAd4 at 83 AD gene.

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.796G>A	p.Ala266Thr	missense	Exon 2 of 2	NP_006488.2	Q14526-2
	HIC1	NM_001098202.1		c.853G>A	p.Ala285Thr	missense	Exon 2 of 2	NP_001091672.1	Q14526-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIC1	ENST00000619757.5	TSL:1 MANE Select	c.796G>A	p.Ala266Thr	missense	Exon 2 of 2	ENSP00000477858.1	Q14526-2
	HIC1	ENST00000399849.4	TSL:1	c.796G>A	p.Ala266Thr	missense	Exon 2 of 2	ENSP00000382742.2	Q14526-2
	HIC1	ENST00000322941.3	TSL:5	c.853G>A	p.Ala285Thr	missense	Exon 2 of 2	ENSP00000314080.3	Q14526-1

Frequencies

GnomAD3 genomes AF: 0.000547 AC: 83 AN: 151848 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000957

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000481 AC: 41 AN: 85186 AF XY: 0.000455

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000543

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000395

GnomAD4 exome AF: 0.000967 AC: 1287 AN: 1331502 Hom.: 0 Cov.: 32 AF XY: 0.000911 AC XY: 598 AN XY: 656446

African (AFR) AF: 0.0000373 AC: 1 AN: 26804

American (AMR) AF: 0.0000335 AC: 1 AN: 29892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23412

East Asian (EAS) AF: 0.00 AC: 0 AN: 28730

South Asian (SAS) AF: 0.0000268 AC: 2 AN: 74620

European-Finnish (FIN) AF: 0.000515 AC: 17 AN: 33018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4354

European-Non Finnish (NFE) AF: 0.00117 AC: 1232 AN: 1055430

Other (OTH) AF: 0.000615 AC: 34 AN: 55242

GnomAD4 genome AF: 0.000547 AC: 83 AN: 151848 Hom.: 0 Cov.: 34 AF XY: 0.000512 AC XY: 38 AN XY: 74158

African (AFR) AF: 0.000314 AC: 13 AN: 41396

American (AMR) AF: 0.000197 AC: 3 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000957 AC: 65 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000654 Hom.: 1

Bravo AF: 0.000499

ExAC AF: 0.000227 AC: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.66
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.020
Sift	Benign	0.56	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.027
MVP		0.072
ClinPred		0.016	T
GERP RS		-6.1
Varity_R		0.041
gMVP		0.11
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs769064912; hg19: chr17-1960780;