ENST00000510626.5:n.10871G>A

Variant names:

• chr4-3240373-G-A
• rs362306
• ENST00000510626.5:n.10871G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000510626.5(HTT):​n.10871G>A variant causes a non coding transcript exon 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (5612 hom., cov: 34)
  • Exomes 𝑓: 0.29 (12200 hom.)
• Consequence: HTT ENST00000510626.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500
• Publications: 19 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 Gene-Disease associations (from GenCC):

• Huntington disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• juvenile Huntington disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.*314G>A		3_prime_UTR_variant	Exon 67 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.*314G>A		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.*314G>A		3_prime_UTR_variant	Exon 67 of 67	1	NM_001388492.1	ENSP00000347184.5

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

African (AFR) AF: 0.0604 AC: 479 AN: 7928

American (AMR) AF: 0.268 AC: 2670 AN: 9946

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 2343 AN: 7882

East Asian (EAS) AF: 0.386 AC: 5683 AN: 14718

South Asian (SAS) AF: 0.200 AC: 6975 AN: 34812

European-Finnish (FIN) AF: 0.424 AC: 5973 AN: 14100

Middle Eastern (MID) AF: 0.133 AC: 151 AN: 1134

European-Non Finnish (NFE) AF: 0.310 AC: 48728 AN: 157288

Other (OTH) AF: 0.288 AC: 4196 AN: 14594

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

African (AFR) AF: 0.0590 AC: 2452 AN: 41590

American (AMR) AF: 0.251 AC: 3836 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1029 AN: 3472

East Asian (EAS) AF: 0.380 AC: 1965 AN: 5174

South Asian (SAS) AF: 0.199 AC: 961 AN: 4828

European-Finnish (FIN) AF: 0.440 AC: 4665 AN: 10600

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20810 AN: 67984

Other (OTH) AF: 0.213 AC: 450 AN: 2112

Alfa AF: 0.267 Hom.: 11662

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
PhyloP100		0.050
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs362306; hg19: chr4-3242100;