rs754481229

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 8P and 10B. PVS1BP6_ModerateBS1BS2

The NM_001388492.1(HTT):c.102_105delGCAG(p.Gln34HisfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 141,172 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.016 ( 36 hom., cov: 25)

Exomes 𝑓: 0.011 ( 249 hom. )

Failed GnomAD Quality Control

Consequence

HTT
NM_001388492.1 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.80

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Huntington disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
Lopes-Maciel-Rodan syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
juvenile Huntington disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HTT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 4-3074926-AGCAG-A is Benign according to our data. Variant chr4-3074926-AGCAG-A is described in ClinVar as [Benign]. Clinvar id is 402953.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (2277/141172) while in subpopulation NFE AF = 0.0237 (1528/64438). AF 95% confidence interval is 0.0227. There are 36 homozygotes in GnomAd4. There are 1027 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.102_105delGCAG	p.Gln34HisfsTer66	frameshift_variant	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.102_105delGCAG	p.Gln34HisfsTer66	frameshift_variant	Exon 1 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.102_105delGCAG	p.Gln34HisfsTer66	frameshift_variant	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2281

AN:

141102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00520

Gnomad AMI

AF:

0.0108

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.0362

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.00741

AC:

728

AN:

98246

AF XY:

0.00762

show subpopulations

Gnomad AFR exome

AF:

0.00233

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.0230

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00883

Gnomad OTH exome

AF:

0.00997

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0113

AC:

15025

AN:

1325628

Hom.:

249

AF XY:

0.0115

AC XY:

7510

AN XY:

653424

show subpopulations

African (AFR)

AF:

0.00323

AC:

AN:

26944

American (AMR)

AF:

0.00590

AC:

194

AN:

32870

Ashkenazi Jewish (ASJ)

AF:

0.0370

AC:

870

AN:

23540

East Asian (EAS)

AF:

0.00

AC:

AN:

31344

South Asian (SAS)

AF:

0.00624

AC:

466

AN:

74672

European-Finnish (FIN)

AF:

0.00720

AC:

245

AN:

34050

Middle Eastern (MID)

AF:

0.0284

AC:

114

AN:

4014

European-Non Finnish (NFE)

AF:

0.0118

AC:

12315

AN:

1043258

Other (OTH)

AF:

0.0134

AC:

734

AN:

54936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

592

1184

1777

2369

2961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0161

AC:

2277

AN:

141172

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1027

AN XY:

68954

show subpopulations

African (AFR)

AF:

0.00521

AC:

193

AN:

37028

American (AMR)

AF:

0.0131

AC:

190

AN:

14526

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

209

AN:

3310

East Asian (EAS)

AF:

0.00

AC:

AN:

4824

South Asian (SAS)

AF:

0.0104

AC:

AN:

4516

European-Finnish (FIN)

AF:

0.00518

AC:

AN:

9452

Middle Eastern (MID)

AF:

0.0355

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0237

AC:

1528

AN:

64438

Other (OTH)

AF:

0.0214

AC:

AN:

1960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: To date, only repeat expansions in this gene are known to be implicated in disease -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=187/13

disease causing (fs/PTC)

(source)

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

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rs754481229

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over