chr4-3240421-C-G

Position:

• chr4-3240421-C-G

Variant summary

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

The NM_001388492.1(HTT):​c.*362C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 322,448 control chromosomes in the GnomAD database, including 13,359 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 0.25 (5798 hom., cov: 34)
  • Exomes 𝑓: 0.28 (7561 hom.)
• Consequence: HTT NM_001388492.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.383

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]

HTT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.*362C>G		3_prime_UTR_variant	67/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.*362C>G		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.*362C>G		3_prime_UTR_variant	67/67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37987 AN: 152168 Hom.: 5793 Cov.: 34

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.284 AC: 48278 AN: 170162 Hom.: 7561 Cov.: 0 AF XY: 0.275 AC XY: 25004 AN XY: 90948

Gnomad4 AFR exome AF: 0.0763

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.390

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.412

Gnomad4 NFE exome AF: 0.303

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.250 AC: 37999 AN: 152286 Hom.: 5798 Cov.: 34 AF XY: 0.252 AC XY: 18787 AN XY: 74462

Gnomad4 AFR AF: 0.0875

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.228

Alfa AF: 0.282 Hom.: 913

Bravo AF: 0.231

Asia WGS AF: 0.318 AC: 1107 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	8.0
DANN	Benign	0.48

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: rs362268; hg19: chr4-3242148;