rs1143646

Positions:

• chr4-3146926-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001388492.1(HTT):​c.3273T>G​(p.Ile1091Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 1,613,944 control chromosomes in the GnomAD database, including 2,183 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.037 (158 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2025 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.427

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HTT. . Gene score misZ 2.7799 (greater than the threshold 3.09). Trascript score misZ 3.7032 (greater than threshold 3.09). GenCC has associacion of gene with Lopes-Maciel-Rodan syndrome, Huntington disease, juvenile Huntington disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.001585871).
• BP6: Variant 4-3146926-T-G is Benign according to our data. Variant chr4-3146926-T-G is described in ClinVar as [Benign]. Clinvar id is 1651223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.3273T>G	p.Ile1091Met	missense_variant	25/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.3279T>G	p.Ile1093Met	missense_variant	25/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.3273T>G	p.Ile1091Met	missense_variant	25/67	1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5574 AN: 152102 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0649

Gnomad FIN AF: 0.0399

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0401 AC: 9998 AN: 249570 Hom.: 281 AF XY: 0.0427 AC XY: 5776 AN XY: 135400

Gnomad AFR exome AF: 0.00859

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0349

Gnomad EAS exome AF: 0.000556

Gnomad SAS exome AF: 0.0602

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0509

Gnomad OTH exome AF: 0.0441

GnomAD4 exome AF: 0.0495 AC: 72415 AN: 1461724 Hom.: 2025 Cov.: 32 AF XY: 0.0501 AC XY: 36413 AN XY: 727170

Gnomad4 AFR exome AF: 0.00744

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0607

Gnomad4 FIN exome AF: 0.0425

Gnomad4 NFE exome AF: 0.0538

Gnomad4 OTH exome AF: 0.0448

GnomAD4 genome AF: 0.0366 AC: 5574 AN: 152220 Hom.: 158 Cov.: 32 AF XY: 0.0370 AC XY: 2750 AN XY: 74420

Gnomad4 AFR AF: 0.00915

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0654

Gnomad4 FIN AF: 0.0399

Gnomad4 NFE AF: 0.0525

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0466 Hom.: 311

Bravo AF: 0.0339

TwinsUK AF: 0.0593 AC: 220

ALSPAC AF: 0.0581 AC: 224

ESP6500AA AF: 0.00891 AC: 35

ESP6500EA AF: 0.0484 AC: 403

ExAC AF: 0.0397 AC: 4805

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0544

EpiControl AF: 0.0509

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.13
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.49	P
Vest4		0.11
MPC		0.39
ClinPred		0.014	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.23

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: rs1143646; hg19: chr4-3148653; COSMIC: COSV61861044;