rs362307

Variant names:

• chr4-3240118-C-T
• rs362307
• NM_001388492.1:c.*59C>T

Variant summary

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

The NM_001388492.1(HTT):​c.*59C>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 0.067 in 1,414,892 control chromosomes in the GnomAD database, including 3,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.054 (327 hom., cov: 34)
  • Exomes 𝑓: 0.069 (3506 hom.)
• Consequence: HTT NM_001388492.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.984

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=-0.84).
• BP6: Variant 4-3240118-C-T is Benign according to our data. Variant chr4-3240118-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.*59C>T		3_prime_UTR_variant	Exon 67 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.*59C>T		3_prime_UTR_variant	Exon 67 of 67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.*59C>T		3_prime_UTR_variant	Exon 67 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 8289 AN: 152244 Hom.: 325 Cov.: 34

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0948

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0615

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.0578

GnomAD4 exome AF: 0.0685 AC: 86540 AN: 1262530 Hom.: 3506 Cov.: 18 AF XY: 0.0669 AC XY: 42001 AN XY: 628198

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0274

Gnomad4 EAS exome AF: 0.000226

Gnomad4 SAS exome AF: 0.0239

Gnomad4 FIN exome AF: 0.0673

Gnomad4 NFE exome AF: 0.0758

Gnomad4 OTH exome AF: 0.0582

GnomAD4 genome AF: 0.0544 AC: 8293 AN: 152362 Hom.: 327 Cov.: 34 AF XY: 0.0546 AC XY: 4070 AN XY: 74502

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0951

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0615

Gnomad4 NFE AF: 0.0761

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0696 Hom.: 64

Bravo AF: 0.0559

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.78
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: rs362307; hg19: chr4-3241845; COSMIC: COSV61859481; COSMIC: COSV61859481;