NM_001388492.1:c.3801C>T

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.3801C>T(p.Leu1267Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,552,978 control chromosomes in the GnomAD database, including 71,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5646 hom., cov: 32)

Exomes 𝑓: 0.30 ( 65628 hom. )

Consequence

HTT
NM_001388492.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.59

Publications

23 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=-0.56).

BP6

Variant 4-3160329-C-T is Benign according to our data. Variant chr4-3160329-C-T is described in ClinVar as Benign. ClinVar VariationId is 1599466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.6 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.3801C>T	p.Leu1267Leu	synonymous_variant	Exon 29 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.3801C>T	p.Leu1267Leu	synonymous_variant	Exon 29 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.3801C>T	p.Leu1267Leu	synonymous_variant	Exon 29 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36523

AN:

152040

Hom.:

5641

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0594

Gnomad AMI

AF:

0.246

Gnomad AMR

AF:

0.251

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.381

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.287

AC:

45697

AN:

159328

AF XY:

0.281

show subpopulations

Gnomad AFR exome

AF:

0.0506

Gnomad AMR exome

AF:

0.286

Gnomad ASJ exome

AF:

0.310

Gnomad EAS exome

AF:

0.379

Gnomad FIN exome

AF:

0.438

Gnomad NFE exome

AF:

0.299

Gnomad OTH exome

AF:

0.274

GnomAD4 exome

AF:

0.300

AC:

420467

AN:

1400820

Hom.:

65628

Cov.:

AF XY:

0.297

AC XY:

205228

AN XY:

691090

show subpopulations

African (AFR)

AF:

0.0468

AC:

1498

AN:

31992

American (AMR)

AF:

0.277

AC:

9939

AN:

35856

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

7738

AN:

25164

East Asian (EAS)

AF:

0.373

AC:

13598

AN:

36452

South Asian (SAS)

AF:

0.187

AC:

14851

AN:

79384

European-Finnish (FIN)

AF:

0.428

AC:

21194

AN:

49482

Middle Eastern (MID)

AF:

0.124

AC:

708

AN:

5700

European-Non Finnish (NFE)

AF:

0.310

AC:

334597

AN:

1078738

Other (OTH)

AF:

0.282

AC:

16344

AN:

58052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

14446

28893

43339

57786

72232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11102

22204

33306

44408

55510

<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:

0.240

AC:

36530

AN:

152158

Hom.:

5646

Cov.:

AF XY:

0.243

AC XY:

18051

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0592

AC:

2460

AN:

41554

American (AMR)

AF:

0.252

AC:

3846

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

1086

AN:

3470

East Asian (EAS)

AF:

0.381

AC:

1965

AN:

5162

South Asian (SAS)

AF:

0.190

AC:

917

AN:

4830

European-Finnish (FIN)

AF:

0.441

AC:

4661

AN:

10574

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.307

AC:

20861

AN:

67966

Other (OTH)

AF:

0.222

AC:

467

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1310

2621

3931

5242

6552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.269

Hom.:

6815

Bravo

AF:

0.220

Asia WGS

AF:

0.304

AC:

1057

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.2

(source)

DANN

Benign

0.47

PhyloP100

1.6

PromoterAI

0.014

Neutral

(source)

Mutation Taster

=100/0

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