rs362272

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001388492.1(HTT):c.8356G>A(p.Val2786Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,610,054 control chromosomes in the GnomAD database, including 73,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.24 ( 5575 hom., cov: 34)

Exomes 𝑓: 0.30 ( 67861 hom. )

Consequence

HTT
NM_001388492.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.42

Variant links:

Genes affected

HTT (HGNC:4851): (huntingtin) Huntingtin is a disease gene linked to Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological. The huntingtin locus is large, spanning 180 kb and consisting of 67 exons. The huntingtin gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript of approximately 10.3 kb is more widely expressed. The genetic defect leading to Huntington's disease may not necessarily eliminate transcription, but may confer a new property on the mRNA or alter the function of the protein. One candidate is the huntingtin-associated protein-1, highly expressed in brain, which has increased affinity for huntingtin protein with expanded polyglutamine repeats. This gene contains an upstream open reading frame in the 5' UTR that inhibits expression of the huntingtin gene product through translational repression. [provided by RefSeq, Jul 2016]

HTT links:

HTT (HGNC:):

HTT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HTT. . Gene score misZ 2.7799 (greater than the threshold 3.09). Trascript score misZ 3.7032 (greater than threshold 3.09). GenCC has associacion of gene with Lopes-Maciel-Rodan syndrome, Huntington disease, juvenile Huntington disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010347664).

BP6

Variant 4-3233253-G-A is Benign according to our data. Variant chr4-3233253-G-A is described in ClinVar as [Benign]. Clinvar id is 1531045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3233253-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1 linkuse as main transcript	c.8356G>A	p.Val2786Ile	missense_variant	61/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 linkuse as main transcript	c.8356G>A	p.Val2786Ile	missense_variant	61/67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 linkuse as main transcript	c.8356G>A	p.Val2786Ile	missense_variant	61/67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36286

AN:

152152

Hom.:

5571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0584

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.203

GnomAD3 exomes

AF:

0.287

AC:

71438

AN:

249088

Hom.:

11258

AF XY:

0.283

AC XY:

38326

AN XY:

135288

show subpopulations

Gnomad AFR exome

AF:

0.0539

Gnomad AMR exome

AF:

0.292

Gnomad ASJ exome

AF:

0.287

Gnomad EAS exome

AF:

0.360

Gnomad SAS exome

AF:

0.199

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.283

GnomAD4 exome

AF:

0.299

AC:

436161

AN:

1457786

Hom.:

67861

Cov.:

AF XY:

0.296

AC XY:

214395

AN XY:

724564

show subpopulations

Gnomad4 AFR exome

AF:

0.0468

Gnomad4 AMR exome

AF:

0.283

Gnomad4 ASJ exome

AF:

0.289

Gnomad4 EAS exome

AF:

0.344

Gnomad4 SAS exome

AF:

0.196

Gnomad4 FIN exome

AF:

0.427

Gnomad4 NFE exome

AF:

0.310

Gnomad4 OTH exome

AF:

0.281

GnomAD4 genome

AF:

0.238

AC:

36292

AN:

152268

Hom.:

5575

Cov.:

AF XY:

0.241

AC XY:

17933

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0582

Gnomad4 AMR

AF:

0.250

Gnomad4 ASJ

AF:

0.297

Gnomad4 EAS

AF:

0.358

Gnomad4 SAS

AF:

0.199

Gnomad4 FIN

AF:

0.441

Gnomad4 NFE

AF:

0.306

Gnomad4 OTH

AF:

0.210

Alfa

AF:

0.282

Hom.:

14901

Bravo

AF:

0.218

TwinsUK

AF:

0.307

AC:

1139

ALSPAC

AF:

0.310

AC:

1194

ESP6500AA

AF:

0.0672

AC:

285

ESP6500EA

AF:

0.296

AC:

2508

ExAC

AF:

0.279

AC:

33753

Asia WGS

AF:

0.301

AC:

1046

AN:

3478

EpiCase

AF:

0.293

EpiControl

AF:

0.286

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.060

DANN

Benign

0.75

DEOGEN2

Benign

0.11

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.17

PrimateAI

Benign

0.21

PROVEAN

Benign

0.070

REVEL

Benign

0.069

Sift

Benign

0.63

Sift4G

Benign

0.80

Polyphen

0.0020

Vest4

0.024

MPC

0.31

ClinPred

0.0030

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.041

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

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