chr12-122855095-C-G

Position:

• chr12-122855095-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003959.3(HIP1R):​c.819C>G​(p.Phe273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HIP1R NM_003959.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIP1R	NM_003959.3	c.819C>G	p.Phe273Leu	missense_variant	10/32	ENST00000253083.9	NP_003950.1
HIP1R	NM_001303097.2	c.819C>G	p.Phe273Leu	missense_variant	10/18		NP_001290026.1
HIP1R	NM_001303099.2	c.783C>G	p.Phe261Leu	missense_variant	10/18		NP_001290028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIP1R	ENST00000253083.9	c.819C>G	p.Phe273Leu	missense_variant	10/32	1	NM_003959.3	ENSP00000253083.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.819C>G (p.F273L) alteration is located in exon 10 (coding exon 10) of the HIP1R gene. This alteration results from a C to G substitution at nucleotide position 819, causing the phenylalanine (F) at amino acid position 273 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.66		Loss of methylation at K274 (P = 0.0294);
MVP		0.30
MPC		0.52
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.88
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-123339642;