4-3241491-C-T

Variant names:

• chr4-3241491-C-T
• rs362267
• ENST00000510626.5:n.11989C>T

Variant summary

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

The ENST00000510626.5(HTT):​n.11989C>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 0.245 in 152,266 control chromosomes in the GnomAD database, including 5,625 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: 0.45 (13 hom.)
• Consequence: HTT ENST00000510626.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• Publications: 10 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.*1432C>T		3_prime_UTR_variant	Exon 67 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.*1432C>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.*1432C>T		3_prime_UTR_variant	Exon 67 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37185 AN: 152002 Hom.: 5608 Cov.: 34

Gnomad AFR AF: 0.0822

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.215

GnomAD4 exome AF: 0.445 AC: 65 AN: 146 Hom.: 13 Cov.: 0 AF XY: 0.447 AC XY: 42 AN XY: 94

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.423 AC: 22 AN: 52

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.514 AC: 37 AN: 72

Other (OTH) AF: 0.500 AC: 3 AN: 6

GnomAD4 genome AF: 0.244 AC: 37193 AN: 152120 Hom.: 5612 Cov.: 34 AF XY: 0.246 AC XY: 18299 AN XY: 74338

African (AFR) AF: 0.0820 AC: 3404 AN: 41516

American (AMR) AF: 0.251 AC: 3831 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1028 AN: 3470

East Asian (EAS) AF: 0.351 AC: 1807 AN: 5148

South Asian (SAS) AF: 0.192 AC: 926 AN: 4824

European-Finnish (FIN) AF: 0.441 AC: 4664 AN: 10576

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20821 AN: 67980

Other (OTH) AF: 0.222 AC: 469 AN: 2112

Alfa AF: 0.254 Hom.: 1223

Bravo AF: 0.225

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.60
PhyloP100		0.20
Mutation Taster		=99/1	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: rs362267; hg19: chr4-3243218;