4-3146843-G-A

Variant names:

• chr4-3146843-G-A
• rs35892913
• NM_001388492.1:c.3190G>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.3190G>A​(p.Val1064Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0531 in 1,613,910 control chromosomes in the GnomAD database, including 2,535 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (171 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2364 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.74
• Publications: 17 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=0.0027657151).
• BP6: Variant 4-3146843-G-A is Benign according to our data. Variant chr4-3146843-G-A is described in ClinVar as Benign. ClinVar VariationId is 1569339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.059 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.3190G>A	p.Val1064Ile	missense	Exon 25 of 67	NP_001375421.1
	HTT	NM_002111.8		c.3190G>A	p.Val1064Ile	missense	Exon 25 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.3190G>A	p.Val1064Ile	missense	Exon 25 of 67	ENSP00000347184.5
	HTT	ENST00000510626.5	TSL:1	n.3289G>A		non_coding_transcript_exon	Exon 12 of 53
	HTT	ENST00000681528.1		c.2932G>A	p.Val978Ile	missense	Exon 25 of 68	ENSP00000506116.1

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6264 AN: 152166 Hom.: 171 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0531

GnomAD2 exomes AF: 0.0428 AC: 10682 AN: 249568 AF XY: 0.0434

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0414

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0503

GnomAD4 exome AF: 0.0543 AC: 79437 AN: 1461626 Hom.: 2364 Cov.: 31 AF XY: 0.0534 AC XY: 38814 AN XY: 727120

African (AFR) AF: 0.00992 AC: 332 AN: 33480

American (AMR) AF: 0.0402 AC: 1796 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 832 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0200 AC: 1729 AN: 86246

European-Finnish (FIN) AF: 0.0408 AC: 2177 AN: 53412

Middle Eastern (MID) AF: 0.0508 AC: 293 AN: 5768

European-Non Finnish (NFE) AF: 0.0623 AC: 69240 AN: 1111770

Other (OTH) AF: 0.0502 AC: 3031 AN: 60390

GnomAD4 genome AF: 0.0411 AC: 6265 AN: 152284 Hom.: 171 Cov.: 32 AF XY: 0.0396 AC XY: 2949 AN XY: 74458

African (AFR) AF: 0.0122 AC: 505 AN: 41554

American (AMR) AF: 0.0520 AC: 796 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4824

European-Finnish (FIN) AF: 0.0439 AC: 466 AN: 10604

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0605 AC: 4115 AN: 68022

Other (OTH) AF: 0.0526 AC: 111 AN: 2112

Alfa AF: 0.0530 Hom.: 546

Bravo AF: 0.0406

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0615 AC: 237

ESP6500AA AF: 0.0134 AC: 54

ESP6500EA AF: 0.0594 AC: 496

ExAC AF: 0.0427 AC: 5157

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0663

EpiControl AF: 0.0705

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	0.082
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.37
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.064
Sift	Benign	0.48	T
Sift4G	Benign	0.69	T
Polyphen		0.042	B
Vest4		0.067
MPC		0.31
ClinPred		0.000041	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.29
Mutation Taster		=99/1	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: rs35892913; hg19: chr4-3148570; COSMIC: COSV61861260;