4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001388492.1(HTT):c.87_110dupGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln30_Gln37dup) variant causes a disruptive inframe insertion change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0070 ( 4 hom., cov: 0)

Exomes 𝑓: 0.0026 ( 41 hom. )

Consequence

HTT
NM_001388492.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.84

Publications

6 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: Benign. The variant received -9 ACMG points.

BP6

Variant 4-3074876-C-CCAGCAGCAGCAGCAGCAGCAGCAG is Benign according to our data. Variant chr4-3074876-C-CCAGCAGCAGCAGCAGCAGCAGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3779750.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00701 (924/131880) while in subpopulation AMR AF = 0.00843 (113/13412). AF 95% confidence interval is 0.00754. There are 4 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.87_110dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln30_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	NP_001375421.1
	HTT	NM_002111.8		c.87_110dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln30_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	NP_002102.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HTT	ENST00000355072.11	TSL:1 MANE Select	c.87_110dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln30_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENSP00000347184.5
HTT	ENST00000680291.1		n.232_255dupGCAGCAGCAGCAGCAGCAGCAGCA		non_coding_transcript_exon	Exon 1 of 41
HTT	ENST00000681528.1		c.6-12027_6-12004dupGCAGCAGCAGCAGCAGCAGCAGCA		intron	N/A	ENSP00000506116.1

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

925

AN:

131782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00613

Gnomad AMI

AF:

0.00750

Gnomad AMR

AF:

0.00851

Gnomad ASJ

AF:

0.00533

Gnomad EAS

AF:

0.00169

Gnomad SAS

AF:

0.00460

Gnomad FIN

AF:

0.00394

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00813

Gnomad OTH

AF:

0.00947

GnomAD4 exome

AF:

0.00259

AC:

3174

AN:

1225730

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1646

AN XY:

608074

show subpopulations

African (AFR)

AF:

0.00225

AC:

AN:

25808

American (AMR)

AF:

0.00383

AC:

116

AN:

30300

Ashkenazi Jewish (ASJ)

AF:

0.00290

AC:

AN:

22730

East Asian (EAS)

AF:

0.00175

AC:

AN:

29096

South Asian (SAS)

AF:

0.00312

AC:

225

AN:

72224

European-Finnish (FIN)

AF:

0.00455

AC:

148

AN:

32498

Middle Eastern (MID)

AF:

0.00423

AC:

AN:

3784

European-Non Finnish (NFE)

AF:

0.00239

AC:

2293

AN:

957466

Other (OTH)

AF:

0.00388

AC:

201

AN:

51824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

196

293

391

489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00701

AC:

924

AN:

131880

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

431

AN XY:

63424

show subpopulations

African (AFR)

AF:

0.00611

AC:

217

AN:

35526

American (AMR)

AF:

0.00843

AC:

113

AN:

13412

Ashkenazi Jewish (ASJ)

AF:

0.00533

AC:

AN:

3190

East Asian (EAS)

AF:

0.00170

AC:

AN:

4124

South Asian (SAS)

AF:

0.00460

AC:

AN:

3910

European-Finnish (FIN)

AF:

0.00394

AC:

AN:

7368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00813

AC:

500

AN:

61482

Other (OTH)

AF:

0.00936

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

452

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Huntington disease (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over