4-3233253-G-A

Variant names:

• chr4-3233253-G-A
• rs362272
• NM_001388492.1:c.8356G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001388492.1(HTT):​c.8356G>A​(p.Val2786Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,610,054 control chromosomes in the GnomAD database, including 73,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5575 hom., cov: 34)
  • Exomes 𝑓: 0.30 (67861 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42
• Publications: 44 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010347664).
• BP6: Variant 4-3233253-G-A is Benign according to our data. Variant chr4-3233253-G-A is described in ClinVar as Benign. ClinVar VariationId is 1531045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.8356G>A	p.Val2786Ile	missense	Exon 61 of 67	NP_001375421.1
	HTT	NM_002111.8		c.8356G>A	p.Val2786Ile	missense	Exon 61 of 67	NP_002102.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.8356G>A	p.Val2786Ile	missense	Exon 61 of 67	ENSP00000347184.5
	HTT	ENST00000510626.5	TSL:1	n.9484G>A		non_coding_transcript_exon	Exon 47 of 53
	HTT	ENST00000681528.1		c.8188G>A	p.Val2730Ile	missense	Exon 62 of 68	ENSP00000506116.1

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36286 AN: 152152 Hom.: 5571 Cov.: 34

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.287 AC: 71438 AN: 249088 AF XY: 0.283

Gnomad AFR exome AF: 0.0539

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.299 AC: 436161 AN: 1457786 Hom.: 67861 Cov.: 36 AF XY: 0.296 AC XY: 214395 AN XY: 724564

African (AFR) AF: 0.0468 AC: 1567 AN: 33450

American (AMR) AF: 0.283 AC: 12624 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7528 AN: 26090

East Asian (EAS) AF: 0.344 AC: 13638 AN: 39602

South Asian (SAS) AF: 0.196 AC: 16847 AN: 86144

European-Finnish (FIN) AF: 0.427 AC: 22494 AN: 52638

Middle Eastern (MID) AF: 0.118 AC: 680 AN: 5762

European-Non Finnish (NFE) AF: 0.310 AC: 343907 AN: 1109284

Other (OTH) AF: 0.281 AC: 16876 AN: 60142

GnomAD4 genome AF: 0.238 AC: 36292 AN: 152268 Hom.: 5575 Cov.: 34 AF XY: 0.241 AC XY: 17933 AN XY: 74434

African (AFR) AF: 0.0582 AC: 2421 AN: 41576

American (AMR) AF: 0.250 AC: 3822 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1031 AN: 3472

East Asian (EAS) AF: 0.358 AC: 1852 AN: 5174

South Asian (SAS) AF: 0.199 AC: 962 AN: 4832

European-Finnish (FIN) AF: 0.441 AC: 4679 AN: 10600

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20837 AN: 67996

Other (OTH) AF: 0.210 AC: 443 AN: 2112

Alfa AF: 0.273 Hom.: 20181

Bravo AF: 0.218

TwinsUK AF: 0.307 AC: 1139

ALSPAC AF: 0.310 AC: 1194

ESP6500AA AF: 0.0672 AC: 285

ESP6500EA AF: 0.296 AC: 2508

ExAC AF: 0.279 AC: 33753

Asia WGS AF: 0.301 AC: 1046 AN: 3478

EpiCase AF: 0.293

EpiControl AF: 0.286

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.060
DANN	Benign	0.75
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N
PhyloP100		1.4
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.069
Sift	Benign	0.63	T
Sift4G	Benign	0.80	T
Polyphen		0.0020	B
Vest4		0.024
MPC		0.31
ClinPred		0.0030	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.041
Mutation Taster		=96/4	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: rs362272; hg19: chr4-3234980; COSMIC: COSV61857565; COSMIC: COSV61857565;