rs362308
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001388492.1(HTT):āc.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
NM_001388492.1 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0670
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 -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 |
---|---|---|---|---|---|---|---|---|
HTT | NM_001388492.1 | c.9378T>C | p.Tyr3126= | synonymous_variant | 67/67 | ENST00000355072.11 | NP_001375421.1 | |
HTT | NM_002111.8 | c.9384T>C | p.Tyr3128= | synonymous_variant | 67/67 | NP_002102.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HTT | ENST00000355072.11 | c.9378T>C | p.Tyr3126= | synonymous_variant | 67/67 | 1 | NM_001388492.1 | ENSP00000347184 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000749 AC: 114AN: 152178Hom.: 2 Cov.: 33
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GnomAD3 exomes AF: 0.000707 AC: 161AN: 227610Hom.: 0 AF XY: 0.000731 AC XY: 90AN XY: 123190
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GnomAD4 exome AF: 0.000857 AC: 1242AN: 1449204Hom.: 1 Cov.: 31 AF XY: 0.000835 AC XY: 601AN XY: 719460
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GnomAD4 genome AF: 0.000749 AC: 114AN: 152296Hom.: 2 Cov.: 33 AF XY: 0.000671 AC XY: 50AN XY: 74478
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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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at