chr4-3146843-G-A

Position:

• chr4-3146843-G-A

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.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. 13/20 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 0.041 (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

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=0.0027657151).
• BP6: Variant 4-3146843-G-A is Benign according to our data. Variant chr4-3146843-G-A is described in ClinVar as [Benign]. Clinvar id is 1569339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3146843-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.3190G>A	p.Val1064Ile	missense_variant	25/67	ENST00000355072.11
HTT	NM_002111.8	c.3196G>A	p.Val1066Ile	missense_variant	25/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.3190G>A	p.Val1064Ile	missense_variant	25/67	1	NM_001388492.1	P2

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

GnomAD3 exomes AF: 0.0428 AC: 10682 AN: 249568 Hom.: 317 AF XY: 0.0434 AC XY: 5876 AN XY: 135398

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 SAS exome AF: 0.0179

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

Gnomad4 AFR exome AF: 0.00992

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.0318

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.0408

Gnomad4 NFE exome AF: 0.0623

Gnomad4 OTH exome AF: 0.0502

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

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.0520

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0439

Gnomad4 NFE AF: 0.0605

Gnomad4 OTH AF: 0.0526

Alfa AF: 0.0559 Hom.: 423

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.98	N
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

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: rs35892913; hg19: chr4-3148570; COSMIC: COSV61861260;