4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BA1

The NM_001388492.1(HTT):c.105_110delGCAGCA(p.Gln36_Gln37del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.245 in 1,348,998 control chromosomes in the GnomAD database, including 35,626 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.20 ( 3269 hom., cov: 0)

Exomes 𝑓: 0.25 ( 32357 hom. )

Consequence

HTT
NM_001388492.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign no assertion criteria provided B:2

Conservation

PhyloP100: 5.65

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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001388492.1

BP6

Variant 4-3074876-CCAGCAG-C is Benign according to our data. Variant chr4-3074876-CCAGCAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 1328024.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.105_110delGCAGCA	p.Gln36_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.105_110delGCAGCA	p.Gln36_Gln37del	disruptive_inframe_deletion	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.105_110delGCAGCA	p.Gln36_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

26654

AN:

131118

Hom.:

3269

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.315

Gnomad SAS

AF:

0.413

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.384

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.225

GnomAD4 exome

AF:

0.249

AC:

303610

AN:

1217784

Hom.:

32357

AF XY:

0.252

AC XY:

152292

AN XY:

603946

show subpopulations

African (AFR)

AF:

0.121

AC:

3112

AN:

25688

American (AMR)

AF:

0.212

AC:

6327

AN:

29842

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

6121

AN:

22568

East Asian (EAS)

AF:

0.313

AC:

8890

AN:

28388

South Asian (SAS)

AF:

0.364

AC:

26050

AN:

71538

European-Finnish (FIN)

AF:

0.176

AC:

5622

AN:

31932

Middle Eastern (MID)

AF:

0.264

AC:

991

AN:

3758

European-Non Finnish (NFE)

AF:

0.245

AC:

233808

AN:

952614

Other (OTH)

AF:

0.247

AC:

12689

AN:

51456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

8671

17342

26012

34683

43354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.203

AC:

26660

AN:

131214

Hom.:

3269

Cov.:

AF XY:

0.206

AC XY:

13028

AN XY:

63102

show subpopulations

African (AFR)

AF:

0.117

AC:

4137

AN:

35462

American (AMR)

AF:

0.198

AC:

2641

AN:

13360

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

930

AN:

3174

East Asian (EAS)

AF:

0.315

AC:

1291

AN:

4092

South Asian (SAS)

AF:

0.413

AC:

1610

AN:

3900

European-Finnish (FIN)

AF:

0.176

AC:

1288

AN:

7324

Middle Eastern (MID)

AF:

0.369

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.228

AC:

13923

AN:

61058

Other (OTH)

AF:

0.223

AC:

401

AN:

1802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

819

1637

2456

3274

4093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.179

Hom.:

452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=175/25

polymorphism (auto)

(source)

Splicing

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

Publications

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4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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