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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_001388492.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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 VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388492.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.102_105delGCAG	p.Gln34HisfsTer66	frameshift	Exon 1 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.102_105delGCAG	p.Gln34HisfsTer66	frameshift	Exon 1 of 67	NP_002102.4	P42858

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTT	ENST00000355072.11	TSL:1 MANE Select	c.102_105delGCAG	p.Gln34HisfsTer66	frameshift	Exon 1 of 67	ENSP00000347184.5	P42858
HTT	ENST00000681528.1		c.6-12012_6-12009delGCAG		intron	N/A	ENSP00000506116.1	A0A7P0TAC5
HTT	ENST00000680956.1		c.6-12012_6-12009delGCAG		intron	N/A	ENSP00000506029.1	A0A7P0TA78

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over