rs2276881

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBA1

The NM_002111.8(HTT):c.8157G>A(p.Leu2719Leu) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,613,994 control chromosomes in the GnomAD database, including 8,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.075 ( 839 hom., cov: 33)

Exomes 𝑓: 0.087 ( 8155 hom. )

Consequence

HTT
NM_002111.8 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.13

Publications

17 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 4-3229934-G-A is Benign according to our data. Variant chr4-3229934-G-A is described in ClinVar as Benign. ClinVar VariationId is 2167059.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002111.8. 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.8157G>A	p.Leu2719Leu	synonymous	Exon 60 of 67	NP_001375421.1
	HTT	NM_002111.8		c.8157G>A	p.Leu2719Leu	synonymous	Exon 60 of 67	NP_002102.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HTT	ENST00000355072.11	TSL:1 MANE Select	c.8157G>A	p.Leu2719Leu	synonymous	Exon 60 of 67	ENSP00000347184.5
HTT	ENST00000510626.5	TSL:1	n.9285G>A		non_coding_transcript_exon	Exon 46 of 53
HTT	ENST00000681528.1		c.7989G>A	p.Leu2663Leu	synonymous	Exon 61 of 68	ENSP00000506116.1

Frequencies

GnomAD3 genomes

AF:

0.0755

AC:

11489

AN:

152184

Hom.:

838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.168

Gnomad ASJ

AF:

0.0660

Gnomad EAS

AF:

0.335

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.0458

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0709

Gnomad OTH

AF:

0.0907

GnomAD2 exomes

AF:

0.114

AC:

28321

AN:

249270

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.204

Gnomad ASJ exome

AF:

0.0671

Gnomad EAS exome

AF:

0.336

Gnomad FIN exome

AF:

0.0480

Gnomad NFE exome

AF:

0.0692

Gnomad OTH exome

AF:

0.0931

GnomAD4 exome

AF:

0.0871

AC:

127375

AN:

1461692

Hom.:

8155

Cov.:

AF XY:

0.0885

AC XY:

64362

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0134

AC:

448

AN:

33480

American (AMR)

AF:

0.203

AC:

9058

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0633

AC:

1655

AN:

26134

East Asian (EAS)

AF:

0.354

AC:

14041

AN:

39694

South Asian (SAS)

AF:

0.160

AC:

13841

AN:

86250

European-Finnish (FIN)

AF:

0.0507

AC:

2706

AN:

53418

Middle Eastern (MID)

AF:

0.0650

AC:

375

AN:

5768

European-Non Finnish (NFE)

AF:

0.0715

AC:

79468

AN:

1111846

Other (OTH)

AF:

0.0958

AC:

5783

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

5730

11460

17189

22919

28649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3180

6360

9540

12720

15900

<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:

0.0754

AC:

11490

AN:

152302

Hom.:

839

Cov.:

AF XY:

0.0794

AC XY:

5914

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0157

AC:

651

AN:

41584

American (AMR)

AF:

0.168

AC:

2575

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0660

AC:

229

AN:

3472

East Asian (EAS)

AF:

0.336

AC:

1735

AN:

5168

South Asian (SAS)

AF:

0.161

AC:

777

AN:

4826

European-Finnish (FIN)

AF:

0.0458

AC:

486

AN:

10606

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0709

AC:

4824

AN:

68018

Other (OTH)

AF:

0.0888

AC:

188

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

518

1035

1553

2070

2588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0747

Hom.:

1320

Bravo

AF:

0.0814

Asia WGS

AF:

0.208

AC:

723

AN:

3478

EpiCase

AF:

0.0711

EpiControl

AF:

0.0666

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

9.1

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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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