rs1313770

chr4-3056082-A-Gchr4-3056082-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000664062.1(HTT-AS):n.1380+6352T>C variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 152,078 control chromosomes in the GnomAD database, including 25,070 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 0.57 (25070 hom., cov: 32)
• Consequence: HTT-AS ENST00000664062.1 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.875

Genes affected

HTT-AS (HGNC:37118): (HTT antisense RNA)

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT-AS	ENST00000664062.1	n.1380+6352T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86506 AN: 151960 Hom.: 25028 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.569 AC: 86600 AN: 152078 Hom.: 25070 Cov.: 32 AF XY: 0.568 AC XY: 42246 AN XY: 74340

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.604

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.733

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.597

Alfa AF: 0.543 Hom.: 2688

Bravo AF: 0.580

Asia WGS AF: 0.532 AC: 1849 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	3.3
Dann	Benign	0.56

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1313770; hg19: chr4-3057809;