rs362307

Variant names:

• chr4-3240118-C-T
• rs362307
• ENST00000510626.5:n.10616C>T

Variant summary

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

The ENST00000510626.5(HTT):​n.10616C>T 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 0.067 in 1,414,892 control chromosomes in the GnomAD database, including 3,833 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.054 (327 hom., cov: 34)
  • Exomes 𝑓: 0.069 (3506 hom.)
• Consequence: HTT ENST00000510626.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.984
• Publications: 56 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 (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

African (AFR) AF: 0.0124 AC: 358 AN: 28982

American (AMR) AF: 0.132 AC: 4652 AN: 35282

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 650 AN: 23742

East Asian (EAS) AF: 0.000226 AC: 8 AN: 35332

South Asian (SAS) AF: 0.0239 AC: 1801 AN: 75512

European-Finnish (FIN) AF: 0.0673 AC: 3091 AN: 45930

Middle Eastern (MID) AF: 0.0153 AC: 59 AN: 3848

European-Non Finnish (NFE) AF: 0.0758 AC: 72811 AN: 960474

Other (OTH) AF: 0.0582 AC: 3110 AN: 53428

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

African (AFR) AF: 0.0163 AC: 676 AN: 41594

American (AMR) AF: 0.0951 AC: 1455 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4826

European-Finnish (FIN) AF: 0.0615 AC: 653 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0761 AC: 5178 AN: 68040

Other (OTH) AF: 0.0572 AC: 121 AN: 2116

Alfa AF: 0.0639 Hom.: 126

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
PhyloP100		-0.98
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: rs362307; hg19: chr4-3241845; COSMIC: COSV61859481; COSMIC: COSV61859481;