NM_001388492.1:c.7797A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001388492.1(HTT):c.7797A>G(p.Leu2599Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,154 control chromosomes in the GnomAD database, including 76,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6303 hom., cov: 33)

Exomes 𝑓: 0.31 ( 70025 hom. )

Consequence

HTT
NM_001388492.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.93

Publications

33 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 4-3225692-A-G is Benign according to our data. Variant chr4-3225692-A-G is described in ClinVar as Benign. ClinVar VariationId is 1627136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.93 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.7797A>G	p.Leu2599Leu	synonymous_variant	Exon 57 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.7797A>G	p.Leu2599Leu	synonymous_variant	Exon 57 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.7797A>G	p.Leu2599Leu	synonymous_variant	Exon 57 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41363

AN:

151906

Hom.:

6297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.265

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.464

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.310

Gnomad OTH

AF:

0.235

GnomAD2 exomes

AF:

0.298

AC:

74155

AN:

248722

AF XY:

0.292

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.299

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.457

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.293

GnomAD4 exome

AF:

0.305

AC:

445815

AN:

1461130

Hom.:

70025

Cov.:

AF XY:

0.301

AC XY:

219034

AN XY:

726894

show subpopulations

African (AFR)

AF:

0.149

AC:

5002

AN:

33472

American (AMR)

AF:

0.291

AC:

13004

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7898

AN:

26116

East Asian (EAS)

AF:

0.368

AC:

14591

AN:

39676

South Asian (SAS)

AF:

0.193

AC:

16618

AN:

86232

European-Finnish (FIN)

AF:

0.449

AC:

23948

AN:

53374

Middle Eastern (MID)

AF:

0.137

AC:

792

AN:

5764

European-Non Finnish (NFE)

AF:

0.312

AC:

346299

AN:

1111482

Other (OTH)

AF:

0.293

AC:

17663

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

14707

29415

44122

58830

73537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11386

22772

34158

45544

56930

<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:

0.272

AC:

41393

AN:

152024

Hom.:

6303

Cov.:

AF XY:

0.274

AC XY:

20385

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.161

AC:

6686

AN:

41476

American (AMR)

AF:

0.265

AC:

4059

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1065

AN:

3464

East Asian (EAS)

AF:

0.379

AC:

1945

AN:

5136

South Asian (SAS)

AF:

0.196

AC:

942

AN:

4814

European-Finnish (FIN)

AF:

0.464

AC:

4896

AN:

10560

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.309

AC:

21035

AN:

67968

Other (OTH)

AF:

0.241

AC:

510

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1488

2975

4463

5950

7438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.284

Hom.:

10003

Bravo

AF:

0.253

Asia WGS

AF:

0.314

AC:

1092

AN:

3478

EpiCase

AF:

0.295

EpiControl

AF:

0.289

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.3

(source)

DANN

Benign

0.75

PhyloP100

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=92/8

polymorphism (auto)

(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

Publications

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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