chr4-3240433-C-G

Variant names:

• chr4-3240433-C-G
• rs362305
• NM_001388492.1:c.*374C>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.*374C>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 0.141 in 307,298 control chromosomes in the GnomAD database, including 4,285 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 0.17 (3012 hom., cov: 34)
  • Exomes 𝑓: 0.11 (1273 hom.)
• Consequence: HTT NM_001388492.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240
• Publications: 5 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.333 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.*374C>G		3_prime_UTR	Exon 67 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.*374C>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.*374C>G		3_prime_UTR	Exon 67 of 67	ENSP00000347184.5	P42858
	HTT	ENST00000510626.5	TSL:1	n.10931C>G		non_coding_transcript_exon	Exon 53 of 53
	HTT	ENST00000681528.1		c.*374C>G		3_prime_UTR	Exon 68 of 68	ENSP00000506116.1	A0A7P0TAC5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25554 AN: 152182 Hom.: 3003 Cov.: 34

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.00577

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.114 AC: 17595 AN: 154998 Hom.: 1273 Cov.: 0 AF XY: 0.111 AC XY: 9238 AN XY: 82878

African (AFR) AF: 0.355 AC: 1678 AN: 4730

American (AMR) AF: 0.0915 AC: 542 AN: 5926

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 634 AN: 3954

East Asian (EAS) AF: 0.00632 AC: 40 AN: 6326

South Asian (SAS) AF: 0.105 AC: 2702 AN: 25840

European-Finnish (FIN) AF: 0.112 AC: 850 AN: 7576

Middle Eastern (MID) AF: 0.210 AC: 130 AN: 618

European-Non Finnish (NFE) AF: 0.109 AC: 10044 AN: 92060

Other (OTH) AF: 0.122 AC: 975 AN: 7968

GnomAD4 genome AF: 0.168 AC: 25587 AN: 152300 Hom.: 3012 Cov.: 34 AF XY: 0.165 AC XY: 12284 AN XY: 74482

African (AFR) AF: 0.337 AC: 14009 AN: 41542

American (AMR) AF: 0.102 AC: 1559 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 526 AN: 3470

East Asian (EAS) AF: 0.00578 AC: 30 AN: 5188

South Asian (SAS) AF: 0.103 AC: 499 AN: 4830

European-Finnish (FIN) AF: 0.110 AC: 1167 AN: 10626

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7348 AN: 68020

Other (OTH) AF: 0.148 AC: 313 AN: 2114

Alfa AF: 0.147 Hom.: 276

Bravo AF: 0.174

Asia WGS AF: 0.0700 AC: 241 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.7
DANN	Benign	0.75
PhyloP100		0.24
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: rs362305; hg19: chr4-3242160;