rs362306

Positions:

• chr4-3240373-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001388492.1(HTT):​c.*314G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 414,676 control chromosomes in the GnomAD database, including 17,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.24 (5612 hom., cov: 34)
  • Exomes 𝑓: 0.29 (12200 hom.)
• Consequence: HTT NM_001388492.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-3240373-G-A is Benign according to our data. Variant chr4-3240373-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.*314G>A		3_prime_UTR_variant	67/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.*314G>A		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.*314G>A		3_prime_UTR_variant	67/67	1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36406 AN: 152156 Hom.: 5608 Cov.: 34

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.294 AC: 77198 AN: 262402 Hom.: 12200 Cov.: 0 AF XY: 0.287 AC XY: 39756 AN XY: 138484

Gnomad4 AFR exome AF: 0.0604

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.239 AC: 36411 AN: 152274 Hom.: 5612 Cov.: 34 AF XY: 0.242 AC XY: 18013 AN XY: 74458

Gnomad4 AFR AF: 0.0590

Gnomad4 AMR AF: 0.251

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.440

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.213

Alfa AF: 0.279 Hom.: 7329

Bravo AF: 0.219

Asia WGS AF: 0.308 AC: 1071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.21
DANN	Benign	0.47

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: rs362306; hg19: chr4-3242100;