Variant chr12-122855126-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003959.3(HIP1R):c.850G>A(p.Glu284Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000291 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

HIP1R
NM_003959.3 missense, splice_region

Scores

Splicing: ADA: 0.7077

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.68

Variant links:

Genes affected

HIP1R (HGNC:18415): (huntingtin interacting protein 1 related) Enables several functions, including phosphatidylinositol phosphate binding activity; phosphatidylinositol-3,4-bisphosphate binding activity; and protein homodimerization activity. Involved in several processes, including positive regulation of signal transduction; protein stabilization; and regulation of organelle organization. Located in clathrin-coated vesicle; cytosol; and ruffle membrane. [provided by Alliance of Genome Resources, Apr 2022]

HIP1R links:

HIP1R (HGNC:):

HIP1R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIP1R	NM_003959.3 linkuse as main transcript	c.850G>A	p.Glu284Lys	missense_variant, splice_region_variant	10/32	ENST00000253083.9	NP_003950.1	O75146-1
HIP1R	NM_001303097.2 linkuse as main transcript	c.850G>A	p.Glu284Lys	missense_variant, splice_region_variant	10/18		NP_001290026.1	O75146-2B4DPL0B3KQW8
HIP1R	NM_001303099.2 linkuse as main transcript	c.814G>A	p.Glu272Lys	missense_variant, splice_region_variant	10/18		NP_001290028.1	B3KQW8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIP1R	ENST00000253083.9 linkuse as main transcript	c.850G>A	p.Glu284Lys	missense_variant, splice_region_variant	10/32	1	NM_003959.3	ENSP00000253083.4		O75146-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250946

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461238

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000125

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.850G>A (p.E284K) alteration is located in exon 10 (coding exon 10) of the HIP1R gene. This alteration results from a G to A substitution at nucleotide position 850, causing the glutamic acid (E) at amino acid position 284 to be replaced by a lysine (K). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.20

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.56

MutPred

0.53

Gain of methylation at E284 (P = 0.0098);

MVP

0.37

MPC

0.35

ClinPred

0.82

GERP RS

4.6

Varity_R

0.57

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.71

dbscSNV1_RF

Pathogenic

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over