Variant rs1065745 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_001388492.1(HTT):c.1188C>T(p.Thr396=) 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, single submitter B:1

Conservation

PhyloP100: -0.217

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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_single_submitter, 1 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/exons	MANE	UniProt
HTT	NM_001388492.1 linkuse as main transcript	c.1188C>T	p.Thr396=	synonymous_variant	9/67	ENST00000355072.11
HTT	NM_002111.8 linkuse as main transcript	c.1194C>T	p.Thr398=	synonymous_variant	9/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11 linkuse as main transcript	c.1188C>T	p.Thr396=	synonymous_variant	9/67	1	NM_001388492.1	P2

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

GnomAD3 exomes

AF:

0.0469

AC:

11705

AN:

249534

Hom.:

383

AF XY:

0.0476

AC XY:

6442

AN XY:

135388

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 SAS exome

AF:

0.0716

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

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.0242

Gnomad4 ASJ exome

AF:

0.0319

Gnomad4 EAS exome

AF:

0.00426

Gnomad4 SAS exome

AF:

0.0698

Gnomad4 FIN exome

AF:

0.0619

Gnomad4 NFE exome

AF:

0.0397

Gnomad4 OTH exome

AF:

0.0478

GnomAD4 genome

AF:

0.0676

AC:

10291

AN:

152208

Hom.:

478

Cov.:

AF XY:

0.0685

AC XY:

5098

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.0362

Gnomad4 ASJ

AF:

0.0357

Gnomad4 EAS

AF:

0.00522

Gnomad4 SAS

AF:

0.0752

Gnomad4 FIN

AF:

0.0678

Gnomad4 NFE

AF:

0.0414

Gnomad4 OTH

AF:

0.0553

Alfa

AF:

0.0522

Hom.:

150

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:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.3

DANN

Benign

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over