chr4-3223644-A-C

Position:

• chr4-3223644-A-C

Variant summary

Our verdict is Benign. Variant got -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

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=-0.93).
• 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/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.7625+84A>C		intron_variant		ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.7625+84A>C		intron_variant			NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.7625+84A>C		intron_variant		1	NM_001388492.1	ENSP00000347184	P2

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

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.448

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.303

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

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.263

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

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: rs82334; hg19: chr4-3225371;