rs363088

Positions:

• chr4-3208603-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-3208603-A-T is Benign according to our data. Variant chr4-3208603-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.6153-170A>T		intron_variant		ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.6153-170A>T		intron_variant			NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.6153-170A>T		intron_variant		1	NM_001388492.1	ENSP00000347184	P2

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

Gnomad4 AFR AF: 0.0593

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.389

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.218

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.047
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs363088; hg19: chr4-3210330;