rs362308

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001388492.1(HTT):ā€‹c.9378T>Cā€‹(p.Tyr3126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 1,601,500 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00075 ( 2 hom., cov: 33)
Exomes š‘“: 0.00086 ( 1 hom. )

Consequence

HTT
NM_001388492.1 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0670
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 4-3240008-T-C is Benign according to our data. Variant chr4-3240008-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1453852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000749 (114/152296) while in subpopulation AMR AF= 0.00196 (30/15308). AF 95% confidence interval is 0.00141. There are 2 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HTTNM_001388492.1 linkuse as main transcriptc.9378T>C p.Tyr3126= synonymous_variant 67/67 ENST00000355072.11 NP_001375421.1
HTTNM_002111.8 linkuse as main transcriptc.9384T>C p.Tyr3128= synonymous_variant 67/67 NP_002102.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HTTENST00000355072.11 linkuse as main transcriptc.9378T>C p.Tyr3126= synonymous_variant 67/671 NM_001388492.1 ENSP00000347184 P2

Frequencies

GnomAD3 genomes
AF:
0.000749
AC:
114
AN:
152178
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000985
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000707
AC:
161
AN:
227610
Hom.:
0
AF XY:
0.000731
AC XY:
90
AN XY:
123190
show subpopulations
Gnomad AFR exome
AF:
0.000296
Gnomad AMR exome
AF:
0.00157
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000363
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000970
Gnomad OTH exome
AF:
0.00105
GnomAD4 exome
AF:
0.000857
AC:
1242
AN:
1449204
Hom.:
1
Cov.:
31
AF XY:
0.000835
AC XY:
601
AN XY:
719460
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.00176
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000120
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000986
Gnomad4 OTH exome
AF:
0.00115
GnomAD4 genome
AF:
0.000749
AC:
114
AN:
152296
Hom.:
2
Cov.:
33
AF XY:
0.000671
AC XY:
50
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000985
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00105
Hom.:
1
Bravo
AF:
0.00100

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
2.5
DANN
Benign
0.64

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: rs362308; hg19: chr4-3241735; API