chr4-3121347-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001388492.1(HTT):c.1188C>T(p.Thr396Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,613,760 control chromosomes in the GnomAD database, including 2,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 478 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1728 hom. )

Consequence

HTT
NM_001388492.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.217

Publications

8 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 4-3121347-C-T is Benign according to our data. Variant chr4-3121347-C-T is described in ClinVar as [Benign]. Clinvar id is 1600856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.217 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.1188C>T	p.Thr396Thr	synonymous_variant	Exon 9 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.1188C>T	p.Thr396Thr	synonymous_variant	Exon 9 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.1188C>T	p.Thr396Thr	synonymous_variant	Exon 9 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.0675

AC:

10273

AN:

152090

Hom.:

473

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0363

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.00521

Gnomad SAS

AF:

0.0753

Gnomad FIN

AF:

0.0678

Gnomad MID

AF:

0.0637

Gnomad NFE

AF:

0.0414

Gnomad OTH

AF:

0.0559

GnomAD2 exomes

AF:

0.0469

AC:

11705

AN:

249534

AF XY:

0.0476

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0231

Gnomad ASJ exome

AF:

0.0306

Gnomad EAS exome

AF:

0.00534

Gnomad FIN exome

AF:

0.0654

Gnomad NFE exome

AF:

0.0405

Gnomad OTH exome

AF:

0.0406

GnomAD4 exome

AF:

0.0433

AC:

63230

AN:

1461552

Hom.:

1728

Cov.:

AF XY:

0.0434

AC XY:

31573

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.132

AC:

4401

AN:

33464

American (AMR)

AF:

0.0242

AC:

1083

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0319

AC:

834

AN:

26134

East Asian (EAS)

AF:

0.00426

AC:

169

AN:

39700

South Asian (SAS)

AF:

0.0698

AC:

6020

AN:

86252

European-Finnish (FIN)

AF:

0.0619

AC:

3304

AN:

53418

Middle Eastern (MID)

AF:

0.0643

AC:

371

AN:

5766

European-Non Finnish (NFE)

AF:

0.0397

AC:

44162

AN:

1111714

Other (OTH)

AF:

0.0478

AC:

2886

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

3005

6009

9014

12018

15023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0676

AC:

10291

AN:

152208

Hom.:

478

Cov.:

AF XY:

0.0685

AC XY:

5098

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.133

AC:

5544

AN:

41534

American (AMR)

AF:

0.0362

AC:

553

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3470

East Asian (EAS)

AF:

0.00522

AC:

AN:

5172

South Asian (SAS)

AF:

0.0752

AC:

362

AN:

4816

European-Finnish (FIN)

AF:

0.0678

AC:

718

AN:

10596

Middle Eastern (MID)

AF:

0.0651

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0414

AC:

2816

AN:

68008

Other (OTH)

AF:

0.0553

AC:

117

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

479

958

1437

1916

2395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0522

Hom.:

184

Bravo

AF:

0.0659

Asia WGS

AF:

0.0490

AC:

171

AN:

3478

EpiCase

AF:

0.0334

EpiControl

AF:

0.0379

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

-0.39

CADD

Benign

9.3

(source)

DANN

Benign

0.39

PhyloP100

-0.22

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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chr4-3121347-C-T

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