4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001388492.1(HTT):c.99_110dupGCAGCAGCAGCA(p.Gln34_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 Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 75 hom., cov: 0)

Exomes 𝑓: 0.010 ( 164 hom. )

Consequence

HTT
NM_001388492.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Lopes-Maciel-Rodan syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -16 ACMG points.

BP6

Variant 4-3074876-C-CCAGCAGCAGCAG is Benign according to our data. Variant chr4-3074876-C-CCAGCAGCAGCAG is described in ClinVar as Benign. ClinVar VariationId is 1690808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0266 (3503/131854) while in subpopulation AMR AF = 0.0397 (532/13404). AF 95% confidence interval is 0.0369. There are 75 homozygotes in GnomAd4. There are 1672 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 75 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.99_110dupGCAGCAGCAGCA	p.Gln34_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.99_110dupGCAGCAGCAGCA	p.Gln34_Gln37dup	disruptive_inframe_insertion	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.99_110dupGCAGCAGCAGCA	p.Gln34_Gln37dup	disruptive_inframe_insertion	Exon 1 of 67	ENSP00000347184.5	P42858
HTT	ENST00000681528.1		c.6-12015_6-12004dupGCAGCAGCAGCA		intron	N/A	ENSP00000506116.1	A0A7P0TAC5
HTT	ENST00000680956.1		c.6-12015_6-12004dupGCAGCAGCAGCA		intron	N/A	ENSP00000506029.1	A0A7P0TA78

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

3497

AN:

131756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0395

Gnomad ASJ

AF:

0.0166

Gnomad EAS

AF:

0.00701

Gnomad SAS

AF:

0.0189

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.0187

Gnomad NFE

AF:

0.0323

Gnomad OTH

AF:

0.0301

GnomAD4 exome

AF:

0.0103

AC:

12565

AN:

1225544

Hom.:

164

Cov.:

AF XY:

0.0111

AC XY:

6749

AN XY:

608000

show subpopulations

African (AFR)

AF:

0.00581

AC:

150

AN:

25808

American (AMR)

AF:

0.0250

AC:

758

AN:

30270

Ashkenazi Jewish (ASJ)

AF:

0.0128

AC:

291

AN:

22734

East Asian (EAS)

AF:

0.00385

AC:

112

AN:

29096

South Asian (SAS)

AF:

0.0115

AC:

829

AN:

72212

European-Finnish (FIN)

AF:

0.0238

AC:

772

AN:

32484

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

3780

European-Non Finnish (NFE)

AF:

0.00929

AC:

8892

AN:

957348

Other (OTH)

AF:

0.0136

AC:

703

AN:

51812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

467

934

1402

1869

2336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0266

AC:

3503

AN:

131854

Hom.:

Cov.:

AF XY:

0.0264

AC XY:

1672

AN XY:

63404

show subpopulations

African (AFR)

AF:

0.0150

AC:

534

AN:

35522

American (AMR)

AF:

0.0397

AC:

532

AN:

13404

Ashkenazi Jewish (ASJ)

AF:

0.0166

AC:

AN:

3190

East Asian (EAS)

AF:

0.00703

AC:

AN:

4124

South Asian (SAS)

AF:

0.0194

AC:

AN:

3908

European-Finnish (FIN)

AF:

0.0271

AC:

200

AN:

7370

Middle Eastern (MID)

AF:

0.0198

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.0323

AC:

1985

AN:

61470

Other (OTH)

AF:

0.0297

AC:

AN:

1816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

147

294

442

589

736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0149

Hom.:

452

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

See cases (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

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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