rs363125

Positions:

chr4-3187820-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001388492.1(HTT):c.5159C>A(p.Thr1720Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,611,318 control chromosomes in the GnomAD database, including 16,012 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.19 ( 4433 hom., cov: 32)

Exomes 𝑓: 0.11 ( 11579 hom. )

Consequence

HTT
NM_001388492.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.3118E-4).

BP6

Variant 4-3187820-C-A is Benign according to our data. Variant chr4-3187820-C-A is described in ClinVar as [Benign]. Clinvar id is 1538968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3187820-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.5159C>A	p.Thr1720Asn	missense_variant	39/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.5159C>A	p.Thr1720Asn	missense_variant	39/67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.5159C>A	p.Thr1720Asn	missense_variant	39/67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.194

AC:

29494

AN:

151990

Hom.:

4408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.424

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00712

Gnomad SAS

AF:

0.0993

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.179

GnomAD3 exomes

AF:

0.119

AC:

29785

AN:

249434

Hom.:

2767

AF XY:

0.117

AC XY:

15832

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.428

Gnomad AMR exome

AF:

0.0739

Gnomad ASJ exome

AF:

0.175

Gnomad EAS exome

AF:

0.00656

Gnomad SAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.106

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.111

AC:

162432

AN:

1459210

Hom.:

11579

Cov.:

AF XY:

0.110

AC XY:

80088

AN XY:

726110

show subpopulations

Gnomad4 AFR exome

AF:

0.442

Gnomad4 AMR exome

AF:

0.0770

Gnomad4 ASJ exome

AF:

0.181

Gnomad4 EAS exome

AF:

0.00572

Gnomad4 SAS exome

AF:

0.0983

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.104

Gnomad4 OTH exome

AF:

0.131

GnomAD4 genome

AF:

0.194

AC:

29560

AN:

152108

Hom.:

4433

Cov.:

AF XY:

0.190

AC XY:

14150

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.425

Gnomad4 AMR

AF:

0.113

Gnomad4 ASJ

AF:

0.181

Gnomad4 EAS

AF:

0.00714

Gnomad4 SAS

AF:

0.0988

Gnomad4 FIN

AF:

0.108

Gnomad4 NFE

AF:

0.109

Gnomad4 OTH

AF:

0.177

Alfa

AF:

0.125

Hom.:

3491

Bravo

AF:

0.204

TwinsUK

AF:

0.0995

AC:

369

ALSPAC

AF:

0.107

AC:

414

ESP6500AA

AF:

0.402

AC:

1484

ESP6500EA

AF:

0.117

AC:

960

ExAC

AF:

0.127

AC:

15306

Asia WGS

AF:

0.0940

AC:

325

AN:

3478

EpiCase

AF:

0.104

EpiControl

AF:

0.116

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 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0040

DANN

Benign

0.22

DEOGEN2

Benign

0.095

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.053

MetaRNN

Benign

0.00043

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.23

PROVEAN

Benign

0.75

REVEL

Benign

0.021

Sift

Benign

0.96

Sift4G

Benign

0.95

Polyphen

0.0

Vest4

0.023

MPC

0.43

ClinPred

0.016

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.11

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