7-75539357-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_005338.7(HIP1):c.3027C>T(p.Tyr1009=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,090 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: HIP1 NM_005338.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.334

Genes affected

HIP1 (HGNC:4913): (huntingtin interacting protein 1) The product of this gene is a membrane-associated protein that functions in clathrin-mediated endocytosis and protein trafficking within the cell. The encoded protein binds to the huntingtin protein in the brain; this interaction is lost in Huntington's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 7-75539357-G-A is Benign according to our data. Variant chr7-75539357-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041842.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.
• BS2: High AC in GnomAd at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIP1	NM_005338.7	c.3027C>T	p.Tyr1009=	synonymous_variant	30/31	ENST00000336926.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIP1	ENST00000336926.11	c.3027C>T	p.Tyr1009=	synonymous_variant	30/31	1	NM_005338.7	P1
HIP1	ENST00000616821.4	c.2940C>T	p.Tyr980=	synonymous_variant	30/31	1
HIP1	ENST00000434438.6	c.2874C>T	p.Tyr958=	synonymous_variant	28/29	2

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00223 AC: 561 AN: 251488 Hom.: 9 AF XY: 0.00283 AC XY: 384 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00119 AC: 1737 AN: 1461824 Hom.: 31 Cov.: 31 AF XY: 0.00163 AC XY: 1188 AN XY: 727220

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00627

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74450

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000801 Hom.: 2

Bravo AF: 0.000389

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HIP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	1.5
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs145864307; hg19: chr7-75168677;