chr4-3240421-C-G

Variant names:

• chr4-3240421-C-G
• rs362268
• NM_001388492.1:c.*362C>G

Variant summary

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

The NM_001388492.1(HTT):​c.*362C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 322,448 control chromosomes in the GnomAD database, including 13,359 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 0.25 (5798 hom., cov: 34)
  • Exomes 𝑓: 0.28 (7561 hom.)
• Consequence: HTT NM_001388492.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.383
• Publications: 10 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 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.*362C>G		3_prime_UTR	Exon 67 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.*362C>G		3_prime_UTR	Exon 67 of 67	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.*362C>G		3_prime_UTR	Exon 67 of 67	ENSP00000347184.5	P42858
	HTT	ENST00000510626.5	TSL:1	n.10919C>G		non_coding_transcript_exon	Exon 53 of 53
	HTT	ENST00000681528.1		c.*362C>G		3_prime_UTR	Exon 68 of 68	ENSP00000506116.1	A0A7P0TAC5

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37987 AN: 152168 Hom.: 5793 Cov.: 34

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.284 AC: 48278 AN: 170162 Hom.: 7561 Cov.: 0 AF XY: 0.275 AC XY: 25004 AN XY: 90948

African (AFR) AF: 0.0763 AC: 398 AN: 5218

American (AMR) AF: 0.269 AC: 1761 AN: 6544

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1380 AN: 4446

East Asian (EAS) AF: 0.390 AC: 2799 AN: 7168

South Asian (SAS) AF: 0.191 AC: 5344 AN: 28020

European-Finnish (FIN) AF: 0.412 AC: 3428 AN: 8322

Middle Eastern (MID) AF: 0.135 AC: 95 AN: 706

European-Non Finnish (NFE) AF: 0.303 AC: 30544 AN: 100958

Other (OTH) AF: 0.288 AC: 2529 AN: 8780

GnomAD4 genome AF: 0.250 AC: 37999 AN: 152286 Hom.: 5798 Cov.: 34 AF XY: 0.252 AC XY: 18787 AN XY: 74462

African (AFR) AF: 0.0875 AC: 3640 AN: 41588

American (AMR) AF: 0.261 AC: 3988 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1138 AN: 3470

East Asian (EAS) AF: 0.382 AC: 1975 AN: 5168

South Asian (SAS) AF: 0.200 AC: 965 AN: 4830

European-Finnish (FIN) AF: 0.441 AC: 4672 AN: 10604

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.307 AC: 20893 AN: 68008

Other (OTH) AF: 0.228 AC: 483 AN: 2114

Alfa AF: 0.282 Hom.: 913

Bravo AF: 0.231

Asia WGS AF: 0.318 AC: 1107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.0
DANN	Benign	0.48
PhyloP100		0.38
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: rs362268; hg19: chr4-3242148;