Variant rs82334 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001388492.1(HTT):c.7625+84A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,247,662 control chromosomes in the GnomAD database, including 62,007 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7370 hom., cov: 33)

Exomes 𝑓: 0.31 ( 54637 hom. )

Consequence

HTT
NM_001388492.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.666

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1 linkuse as main transcript	c.7625+84A>C		intron_variant		ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 linkuse as main transcript	c.7625+84A>C		intron_variant			NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 linkuse as main transcript	c.7625+84A>C		intron_variant		1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45970

AN:

152078

Hom.:

7360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.260

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.396

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.462

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.310

Gnomad OTH

AF:

0.257

GnomAD4 exome

AF:

0.311

AC:

340650

AN:

1095466

Hom.:

54637

AF XY:

0.307

AC XY:

167660

AN XY:

546370

show subpopulations

Gnomad4 AFR exome

AF:

0.249

Gnomad4 AMR exome

AF:

0.295

Gnomad4 ASJ exome

AF:

0.319

Gnomad4 EAS exome

AF:

0.386

Gnomad4 SAS exome

AF:

0.193

Gnomad4 FIN exome

AF:

0.448

Gnomad4 NFE exome

AF:

0.312

Gnomad4 OTH exome

AF:

0.303

GnomAD4 genome

AF:

0.302

AC:

46009

AN:

152196

Hom.:

7370

Cov.:

AF XY:

0.304

AC XY:

22585

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.260

Gnomad4 AMR

AF:

0.281

Gnomad4 ASJ

AF:

0.325

Gnomad4 EAS

AF:

0.396

Gnomad4 SAS

AF:

0.195

Gnomad4 FIN

AF:

0.462

Gnomad4 NFE

AF:

0.310

Gnomad4 OTH

AF:

0.263

Alfa

AF:

0.310

Hom.:

944

Bravo

AF:

0.288

Asia WGS

AF:

0.325

AC:

1131

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.9

DANN

Benign

0.65

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over