rs13102260

Variant names:

• chr4-3074678-G-A
• rs13102260
• ENST00000681528.1:c.6-12261G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 13 publications found

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-AS (HGNC:37118): (HTT antisense RNA)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• 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 rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.-148G>A		upstream_gene_variant		ENST00000355072.11	NP_001375421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.-148G>A		upstream_gene_variant		1	NM_001388492.1	ENSP00000347184.5

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

African (AFR) AF: 0.310 AC: 3813 AN: 12318

American (AMR) AF: 0.104 AC: 802 AN: 7720

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 1638 AN: 11508

East Asian (EAS) AF: 0.0926 AC: 2061 AN: 22266

South Asian (SAS) AF: 0.0303 AC: 743 AN: 24502

European-Finnish (FIN) AF: 0.120 AC: 2774 AN: 23156

Middle Eastern (MID) AF: 0.0909 AC: 186 AN: 2046

European-Non Finnish (NFE) AF: 0.0710 AC: 33253 AN: 468428

Other (OTH) AF: 0.0960 AC: 2643 AN: 27526

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

African (AFR) AF: 0.312 AC: 12831 AN: 41152

American (AMR) AF: 0.102 AC: 1474 AN: 14506

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 502 AN: 3404

East Asian (EAS) AF: 0.122 AC: 501 AN: 4110

South Asian (SAS) AF: 0.0453 AC: 201 AN: 4434

European-Finnish (FIN) AF: 0.116 AC: 1203 AN: 10396

Middle Eastern (MID) AF: 0.0938 AC: 27 AN: 288

European-Non Finnish (NFE) AF: 0.0787 AC: 5264 AN: 66846

Other (OTH) AF: 0.131 AC: 268 AN: 2052

Alfa AF: 0.118 Hom.: 438

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
PhyloP100		0.13
PromoterAI		0.15	Neutral

Splicing

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

Other links and lift over

dbSNP: rs13102260; hg19: chr4-3076405;