rs363088

Variant names:

• chr4-3208603-A-T
• rs363088
• NM_001388492.1:c.6153-170A>T

Variant summary

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

The NM_001388492.1(HTT):​c.6153-170A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,112 control chromosomes in the GnomAD database, including 5,572 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 (5572 hom., cov: 32)
• Consequence: HTT NM_001388492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.740
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388492.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.6153-170A>T		intron	N/A	NP_001375421.1	P42858
	HTT	NM_002111.8		c.6153-170A>T		intron	N/A	NP_002102.4	P42858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.6153-170A>T		intron	N/A	ENSP00000347184.5	P42858
	HTT	ENST00000510626.5	TSL:1	n.7311-200A>T		intron	N/A
	HTT	ENST00000681528.1		c.5985-170A>T		intron	N/A	ENSP00000506116.1	A0A7P0TAC5

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36293 AN: 151994 Hom.: 5568 Cov.: 32

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.211

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.239 AC: 36298 AN: 152112 Hom.: 5572 Cov.: 32 AF XY: 0.241 AC XY: 17914 AN XY: 74358

African (AFR) AF: 0.0593 AC: 2463 AN: 41534

American (AMR) AF: 0.249 AC: 3805 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3468

East Asian (EAS) AF: 0.389 AC: 2016 AN: 5180

South Asian (SAS) AF: 0.191 AC: 923 AN: 4822

European-Finnish (FIN) AF: 0.437 AC: 4614 AN: 10552

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20728 AN: 67956

Other (OTH) AF: 0.218 AC: 459 AN: 2110

Alfa AF: 0.273 Hom.: 822

Bravo AF: 0.219

Asia WGS AF: 0.306 AC: 1064 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.047
DANN	Benign	0.62
PhyloP100		-0.74
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: rs363088; hg19: chr4-3210330;