chr12-122835606-G-T

Position:

• chr12-122835606-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003959.3(HIP1R):​c.56G>T​(p.Ser19Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000068 in 1,176,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HIP1R NM_003959.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17932734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIP1R	NM_003959.3	c.56G>T	p.Ser19Ile	missense_variant	1/32	ENST00000253083.9	NP_003950.1
HIP1R	NM_001303097.2	c.56G>T	p.Ser19Ile	missense_variant	1/18		NP_001290026.1
HIP1R	NM_001303099.2	c.57+600G>T		intron_variant			NP_001290028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIP1R	ENST00000253083.9	c.56G>T	p.Ser19Ile	missense_variant	1/32	1	NM_003959.3	ENSP00000253083.4
HIP1R	ENST00000452196.6	n.126G>T		non_coding_transcript_exon_variant	1/18	1
HIP1R	ENST00000535831.5	n.554+600G>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000680 AC: 8 AN: 1176134 Hom.: 0 Cov.: 35 AF XY: 0.00000694 AC XY: 4 AN XY: 576754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000519

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

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

Sep 20, 2023

The c.56G>T (p.S19I) alteration is located in exon 1 (coding exon 1) of the HIP1R gene. This alteration results from a G to T substitution at nucleotide position 56, causing the serine (S) at amino acid position 19 to be replaced by an isoleucine (I). 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	0.38
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.050
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.010	D
Polyphen		0.77	P
Vest4		0.19
MutPred		0.28		Loss of disorder (P = 0.0149);
MVP		0.15
MPC		0.11
ClinPred		0.81	D
GERP RS		2.7
Varity_R		0.25
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-123320153;