rs13102260

chr4-3074678-G-A

Variant summary

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

The ENST00000681528.1(HTT):c.6-12261G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 747,558 control chromosomes in the GnomAD database, including 4,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (2435 hom., cov: 30)
  • Exomes 𝑓: 0.080 (2554 hom.)
• Consequence: HTT ENST00000681528.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126

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=-0.52).
• BP6: Variant 4-3074678-G-A is Benign according to our data. Variant chr4-3074678-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1			upstream_gene_variant		ENST00000355072.11
HTT	NM_002111.8			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11			upstream_gene_variant		1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22272 AN: 147978 Hom.: 2423 Cov.: 30

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.0478

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0909

Gnomad NFE AF: 0.0788

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.0799 AC: 47913 AN: 599470 Hom.: 2554 Cov.: 8 AF XY: 0.0791 AC XY: 23646 AN XY: 299006

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.0926

Gnomad4 SAS exome AF: 0.0303

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.0710

Gnomad4 OTH exome AF: 0.0960

GnomAD4 genome AF: 0.151 AC: 22314 AN: 148088 Hom.: 2435 Cov.: 30 AF XY: 0.149 AC XY: 10790 AN XY: 72196

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.0453

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0787

Gnomad4 OTH AF: 0.131

Alfa AF: 0.112 Hom.: 363

Bravo AF: 0.154

Asia WGS AF: 0.0980 AC: 340 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Benign	0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13102260; hg19: chr4-3076405;