4-3217326-C-T

Position:

• chr4-3217326-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000355072.11(HTT):​c.7055-439C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,114 control chromosomes in the GnomAD database, including 6,282 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 0.22 (6282 hom., cov: 32)
• Consequence: HTT ENST00000355072.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.7055-439C>T		intron_variant		ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.7055-439C>T		intron_variant			NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.7055-439C>T		intron_variant		1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32708 AN: 151996 Hom.: 6247 Cov.: 32

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.0973

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.216 AC: 32786 AN: 152114 Hom.: 6282 Cov.: 32 AF XY: 0.210 AC XY: 15609 AN XY: 74370

Gnomad4 AFR AF: 0.521

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.0239

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0836

Gnomad4 NFE AF: 0.0972

Gnomad4 OTH AF: 0.192

Alfa AF: 0.157 Hom.: 438

Bravo AF: 0.232

Asia WGS AF: 0.103 AC: 358 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.082
DANN	Benign	0.26

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: rs362277; hg19: chr4-3219053;