rs362336

Positions:

• chr4-3212105-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000355072.11(HTT):​c.6591G>A​(p.Glu2197=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,613,220 control chromosomes in the GnomAD database, including 74,997 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6032 hom., cov: 33)
  • Exomes 𝑓: 0.30 (68965 hom.)
• Consequence: HTT ENST00000355072.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0900

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-3212105-G-A is Benign according to our data. Variant chr4-3212105-G-A is described in ClinVar as [Benign]. Clinvar id is 1599468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.6591G>A	p.Glu2197=	synonymous_variant	48/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.6597G>A	p.Glu2199=	synonymous_variant	48/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.6591G>A	p.Glu2197=	synonymous_variant	48/67	1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40291 AN: 152050 Hom.: 6028 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.295 AC: 73558 AN: 249314 Hom.: 11663 AF XY: 0.289 AC XY: 39118 AN XY: 135284

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.391

Gnomad SAS exome AF: 0.193

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.303 AC: 442319 AN: 1461052 Hom.: 68965 Cov.: 35 AF XY: 0.299 AC XY: 217239 AN XY: 726770

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.190

Gnomad4 FIN exome AF: 0.426

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.265 AC: 40307 AN: 152168 Hom.: 6032 Cov.: 33 AF XY: 0.266 AC XY: 19769 AN XY: 74398

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.306

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.232

Alfa AF: 0.283 Hom.: 2993

Bravo AF: 0.248

Asia WGS AF: 0.313 AC: 1088 AN: 3478

EpiCase AF: 0.293

EpiControl AF: 0.289

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.61
DANN	Benign	0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs362336; hg19: chr4-3213832; COSMIC: COSV61870515;