rs362303

Positions:

• chr4-3240580-C-T

Variant summary

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

The NM_001388492.1(HTT):​c.*521C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 158,060 control chromosomes in the GnomAD database, including 3,086 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 0.17 (3041 hom., cov: 34)
  • Exomes 𝑓: 0.11 (45 hom.)
• Consequence: HTT NM_001388492.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.952

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.*521C>T		3_prime_UTR_variant	67/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.*521C>T		3_prime_UTR_variant	67/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.*521C>T		3_prime_UTR_variant	67/67	1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25710 AN: 152044 Hom.: 3032 Cov.: 34

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0994

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00578

Gnomad SAS AF: 0.0942

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.114 AC: 674 AN: 5898 Hom.: 45 Cov.: 0 AF XY: 0.119 AC XY: 341 AN XY: 2876

Gnomad4 AFR exome AF: 0.337

Gnomad4 AMR exome AF: 0.0891

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0988

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.169 AC: 25739 AN: 152162 Hom.: 3041 Cov.: 34 AF XY: 0.166 AC XY: 12377 AN XY: 74388

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.0992

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.00580

Gnomad4 SAS AF: 0.0937

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.147

Alfa AF: 0.114 Hom.: 1521

Bravo AF: 0.174

Asia WGS AF: 0.0670 AC: 233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs362303; hg19: chr4-3242307; COSMIC: COSV61868815; COSMIC: COSV61868815;