rs362273

Positions:

• chr4-3225692-A-G
• chr4-3225692-A-T

Variant summary

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

The NM_001388492.1(HTT):​c.7797A>G​(p.Leu2599Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,154 control chromosomes in the GnomAD database, including 76,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6303 hom., cov: 33)
  • Exomes 𝑓: 0.31 (70025 hom.)
• Consequence: HTT NM_001388492.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.93

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-3225692-A-G is Benign according to our data. Variant chr4-3225692-A-G is described in ClinVar as [Benign]. Clinvar id is 1627136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3225692-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.7797A>G	p.Leu2599Leu	synonymous_variant	57/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.7797A>G	p.Leu2599Leu	synonymous_variant	57/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.7797A>G	p.Leu2599Leu	synonymous_variant	57/67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41363 AN: 151906 Hom.: 6297 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.235

GnomAD3 exomes AF: 0.298 AC: 74155 AN: 248722 Hom.: 11879 AF XY: 0.292 AC XY: 39446 AN XY: 134994

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.375

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.305 AC: 445815 AN: 1461130 Hom.: 70025 Cov.: 35 AF XY: 0.301 AC XY: 219034 AN XY: 726894

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.291

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.368

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.449

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.272 AC: 41393 AN: 152024 Hom.: 6303 Cov.: 33 AF XY: 0.274 AC XY: 20385 AN XY: 74300

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.464

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.241

Alfa AF: 0.287 Hom.: 8214

Bravo AF: 0.253

Asia WGS AF: 0.314 AC: 1092 AN: 3478

EpiCase AF: 0.295

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	-0.59
CADD	Benign	6.3
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs362273; hg19: chr4-3227419; COSMIC: COSV61864971; COSMIC: COSV61864971;