rs363075

Positions:

• chr4-3135947-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.2677G>A​(p.Gly893Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0526 in 1,603,158 control chromosomes in the GnomAD database, including 2,493 homozygotes. In-silico tool predicts 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 (168 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2325 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.74

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=0.002583623).
• BP6: Variant 4-3135947-G-A is Benign according to our data. Variant chr4-3135947-G-A is described in ClinVar as [Benign]. Clinvar id is 1615277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3135947-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.2677G>A	p.Gly893Arg	missense_variant	20/67	ENST00000355072.11
HTT	NM_002111.8	c.2683G>A	p.Gly895Arg	missense_variant	20/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.2677G>A	p.Gly893Arg	missense_variant	20/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6210 AN: 152172 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0604

Gnomad OTH AF: 0.0530

GnomAD3 exomes AF: 0.0414 AC: 9882 AN: 238800 Hom.: 291 AF XY: 0.0421 AC XY: 5464 AN XY: 129778

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0365

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0000583

Gnomad SAS exome AF: 0.0167

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0603

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0538 AC: 78062 AN: 1450868 Hom.: 2325 Cov.: 29 AF XY: 0.0528 AC XY: 38139 AN XY: 721730

Gnomad4 AFR exome AF: 0.00882

Gnomad4 AMR exome AF: 0.0376

Gnomad4 ASJ exome AF: 0.0309

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0617

Gnomad4 OTH exome AF: 0.0496

GnomAD4 genome AF: 0.0408 AC: 6211 AN: 152290 Hom.: 168 Cov.: 32 AF XY: 0.0393 AC XY: 2925 AN XY: 74466

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0518

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0438

Gnomad4 NFE AF: 0.0604

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0553 Hom.: 356

Bravo AF: 0.0403

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.0133 AC: 49

ESP6500EA AF: 0.0600 AC: 492

ExAC AF: 0.0425 AC: 5135

Asia WGS AF: 0.0110 AC: 38 AN: 3478

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	Uncertain	0.37
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.084
MutPred		0.43		Gain of solvent accessibility (P = 0.0171);
MPC		0.13
ClinPred		0.014	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs363075; hg19: chr4-3137674; COSMIC: COSV61861243;