4-3150086-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001388492.1(HTT):​c.3498+1879C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 152,082 control chromosomes in the GnomAD database, including 6,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

Frequency

Genomes: 𝑓 0.27 ( 6436 hom., cov: 31)

Consequence

HTT
NM_001388492.1 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.163
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]

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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=-0.89).
BP6
Variant 4-3150086-C-T is Benign according to our data. Variant chr4-3150086-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HTTNM_001388492.1 linkuse as main transcriptc.3498+1879C>T intron_variant ENST00000355072.11
HTTNM_002111.8 linkuse as main transcriptc.3498+1879C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HTTENST00000355072.11 linkuse as main transcriptc.3498+1879C>T intron_variant 1 NM_001388492.1 P2

Frequencies

GnomAD3 genomes
AF:
0.270
AC:
41069
AN:
151964
Hom.:
6435
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.115
Gnomad AMI
AF:
0.498
Gnomad AMR
AF:
0.334
Gnomad ASJ
AF:
0.260
Gnomad EAS
AF:
0.461
Gnomad SAS
AF:
0.415
Gnomad FIN
AF:
0.218
Gnomad MID
AF:
0.320
Gnomad NFE
AF:
0.331
Gnomad OTH
AF:
0.278
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.270
AC:
41054
AN:
152082
Hom.:
6436
Cov.:
31
AF XY:
0.273
AC XY:
20296
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.115
Gnomad4 AMR
AF:
0.334
Gnomad4 ASJ
AF:
0.260
Gnomad4 EAS
AF:
0.461
Gnomad4 SAS
AF:
0.414
Gnomad4 FIN
AF:
0.218
Gnomad4 NFE
AF:
0.331
Gnomad4 OTH
AF:
0.274
Alfa
AF:
0.327
Hom.:
10288
Bravo
AF:
0.270
Asia WGS
AF:
0.383
AC:
1330
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
4.3
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.

Other links and lift over

dbSNP: rs11731237; hg19: chr4-3151813; API