chr12-122849897-G-C

Position:

• chr12-122849897-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003959.3(HIP1R):​c.380G>C​(p.Gly127Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HIP1R NM_003959.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.82

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIP1R	NM_003959.3	c.380G>C	p.Gly127Ala	missense_variant	5/32	ENST00000253083.9	NP_003950.1
HIP1R	NM_001303097.2	c.380G>C	p.Gly127Ala	missense_variant	5/18		NP_001290026.1
HIP1R	NM_001303099.2	c.344G>C	p.Gly115Ala	missense_variant	5/18		NP_001290028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIP1R	ENST00000253083.9	c.380G>C	p.Gly127Ala	missense_variant	5/32	1	NM_003959.3	ENSP00000253083.4
HIP1R	ENST00000452196.6	n.450G>C		non_coding_transcript_exon_variant	5/18	1
HIP1R	ENST00000535831.5	n.841G>C		non_coding_transcript_exon_variant	5/18	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461224 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726940

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Dec 05, 2024

The c.380G>C (p.G127A) alteration is located in exon 5 (coding exon 5) of the HIP1R gene. This alteration results from a G to C substitution at nucleotide position 380, causing the glycine (G) at amino acid position 127 to be replaced by an alanine (A). 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	0.60
BayesDel_addAF	Benign	0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0081	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.044	D
Polyphen		0.93	P
Vest4		0.66
MutPred		0.75		Loss of helix (P = 0.1706);
MVP		0.39
MPC		0.40
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.90
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs2033323673; hg19: chr12-123334444;