rs82334

Variant names:

• chr4-3223644-A-C
• rs82334
• NM_001388492.1:c.7625+84A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-3223644-A-C
• chr4-3223644-A-G
• chr4-3223644-A-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.7625+84A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,247,662 control chromosomes in the GnomAD database, including 62,007 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 0.30 (7370 hom., cov: 33)
  • Exomes 𝑓: 0.31 (54637 hom.)
• Consequence: HTT NM_001388492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.666
• Publications: 18 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.7625+84A>C		intron_variant	Intron 55 of 66	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.7625+84A>C		intron_variant	Intron 55 of 66		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.7625+84A>C		intron_variant	Intron 55 of 66	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45970 AN: 152078 Hom.: 7360 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.257

GnomAD4 exome AF: 0.311 AC: 340650 AN: 1095466 Hom.: 54637 AF XY: 0.307 AC XY: 167660 AN XY: 546370

African (AFR) AF: 0.249 AC: 6280 AN: 25188

American (AMR) AF: 0.295 AC: 8095 AN: 27436

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 5835 AN: 18308

East Asian (EAS) AF: 0.386 AC: 14369 AN: 37262

South Asian (SAS) AF: 0.193 AC: 12268 AN: 63718

European-Finnish (FIN) AF: 0.448 AC: 22055 AN: 49246

Middle Eastern (MID) AF: 0.139 AC: 656 AN: 4736

European-Non Finnish (NFE) AF: 0.312 AC: 256822 AN: 822476

Other (OTH) AF: 0.303 AC: 14270 AN: 47096

GnomAD4 genome AF: 0.302 AC: 46009 AN: 152196 Hom.: 7370 Cov.: 33 AF XY: 0.304 AC XY: 22585 AN XY: 74414

African (AFR) AF: 0.260 AC: 10780 AN: 41524

American (AMR) AF: 0.281 AC: 4297 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1129 AN: 3470

East Asian (EAS) AF: 0.396 AC: 2049 AN: 5178

South Asian (SAS) AF: 0.195 AC: 940 AN: 4828

European-Finnish (FIN) AF: 0.462 AC: 4894 AN: 10582

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21103 AN: 68002

Other (OTH) AF: 0.263 AC: 555 AN: 2110

Alfa AF: 0.310 Hom.: 944

Bravo AF: 0.288

Asia WGS AF: 0.325 AC: 1131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.65
PhyloP100		-0.67
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: rs82334; hg19: chr4-3225371; COSMIC: COSV107431559;