Variant chr4-3229934-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBA1

The NM_001388492.1(HTT):c.8157G>A(p.Leu2719=) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,613,994 control chromosomes in the GnomAD database, including 8,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.075 ( 839 hom., cov: 33)

Exomes 𝑓: 0.087 ( 8155 hom. )

Consequence

HTT
NM_001388492.1 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.13

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=-0.41).

BP6

Variant 4-3229934-G-A is Benign according to our data. Variant chr4-3229934-G-A is described in ClinVar as [Benign]. Clinvar id is 2167059.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-3229934-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 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.8157G>A	p.Leu2719=	synonymous_variant	60/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 linkuse as main transcript	c.8163G>A	p.Leu2721=	synonymous_variant	60/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 linkuse as main transcript	c.8157G>A	p.Leu2719=	synonymous_variant	60/67	1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes

AF:

0.0755

AC:

11489

AN:

152184

Hom.:

838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.168

Gnomad ASJ

AF:

0.0660

Gnomad EAS

AF:

0.335

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.0458

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0709

Gnomad OTH

AF:

0.0907

GnomAD3 exomes

AF:

0.114

AC:

28321

AN:

249270

Hom.:

2579

AF XY:

0.112

AC XY:

15118

AN XY:

135268

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.204

Gnomad ASJ exome

AF:

0.0671

Gnomad EAS exome

AF:

0.336

Gnomad SAS exome

AF:

0.161

Gnomad FIN exome

AF:

0.0480

Gnomad NFE exome

AF:

0.0692

Gnomad OTH exome

AF:

0.0931

GnomAD4 exome

AF:

0.0871

AC:

127375

AN:

1461692

Hom.:

8155

Cov.:

AF XY:

0.0885

AC XY:

64362

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.203

Gnomad4 ASJ exome

AF:

0.0633

Gnomad4 EAS exome

AF:

0.354

Gnomad4 SAS exome

AF:

0.160

Gnomad4 FIN exome

AF:

0.0507

Gnomad4 NFE exome

AF:

0.0715

Gnomad4 OTH exome

AF:

0.0958

GnomAD4 genome

AF:

0.0754

AC:

11490

AN:

152302

Hom.:

839

Cov.:

AF XY:

0.0794

AC XY:

5914

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0157

Gnomad4 AMR

AF:

0.168

Gnomad4 ASJ

AF:

0.0660

Gnomad4 EAS

AF:

0.336

Gnomad4 SAS

AF:

0.161

Gnomad4 FIN

AF:

0.0458

Gnomad4 NFE

AF:

0.0709

Gnomad4 OTH

AF:

0.0888

Alfa

AF:

0.0719

Hom.:

781

Bravo

AF:

0.0814

Asia WGS

AF:

0.208

AC:

723

AN:

3478

EpiCase

AF:

0.0711

EpiControl

AF:

0.0666

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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