4-3240545-C-A

Variant names:

• chr4-3240545-C-A
• rs362304
• ENST00000510626.5:n.11043C>A

Variant summary

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

The ENST00000510626.5(HTT):​n.11043C>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 0.181 in 170,884 control chromosomes in the GnomAD database, including 4,193 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 0.19 (4060 hom., cov: 34)
  • Exomes 𝑓: 0.11 (133 hom.)
• Consequence: HTT ENST00000510626.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81
• Publications: 4 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.*486C>A		3_prime_UTR_variant	Exon 67 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.*486C>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.*486C>A		3_prime_UTR_variant	Exon 67 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28837 AN: 152178 Hom.: 4040 Cov.: 34

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.111 AC: 2072 AN: 18588 Hom.: 133 Cov.: 0 AF XY: 0.111 AC XY: 1037 AN XY: 9328

African (AFR) AF: 0.385 AC: 127 AN: 330

American (AMR) AF: 0.0931 AC: 235 AN: 2524

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 55 AN: 350

East Asian (EAS) AF: 0.00602 AC: 4 AN: 664

South Asian (SAS) AF: 0.122 AC: 213 AN: 1740

European-Finnish (FIN) AF: 0.110 AC: 90 AN: 816

Middle Eastern (MID) AF: 0.0962 AC: 5 AN: 52

European-Non Finnish (NFE) AF: 0.109 AC: 1214 AN: 11134

Other (OTH) AF: 0.132 AC: 129 AN: 978

GnomAD4 genome AF: 0.190 AC: 28895 AN: 152296 Hom.: 4060 Cov.: 34 AF XY: 0.186 AC XY: 13821 AN XY: 74476

African (AFR) AF: 0.401 AC: 16635 AN: 41530

American (AMR) AF: 0.113 AC: 1724 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3468

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5186

South Asian (SAS) AF: 0.109 AC: 525 AN: 4830

European-Finnish (FIN) AF: 0.111 AC: 1178 AN: 10624

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7746 AN: 68034

Other (OTH) AF: 0.166 AC: 350 AN: 2114

Alfa AF: 0.117 Hom.: 460

Bravo AF: 0.199

Asia WGS AF: 0.0770 AC: 266 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	0.13
DANN	Benign	0.57
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs362304; hg19: chr4-3242272;