rs362273

Variant names:

• chr4-3225692-A-G
• rs362273
• NM_001388492.1:c.7797A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-3225692-A-G
• chr4-3225692-A-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• Huntington disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• juvenile Huntington disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1627136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388492.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.7797A>G	p.Leu2599Leu	synonymous	Exon 57 of 67	NP_001375421.1
	HTT	NM_002111.8		c.7797A>G	p.Leu2599Leu	synonymous	Exon 57 of 67	NP_002102.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.7797A>G	p.Leu2599Leu	synonymous	Exon 57 of 67	ENSP00000347184.5
	HTT	ENST00000510626.5	TSL:1	n.8925A>G		non_coding_transcript_exon	Exon 43 of 53
	HTT	ENST00000681528.1		c.7629A>G	p.Leu2543Leu	synonymous	Exon 58 of 68	ENSP00000506116.1

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

GnomAD2 exomes AF: 0.298 AC: 74155 AN: 248722 AF XY: 0.292

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 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

African (AFR) AF: 0.149 AC: 5002 AN: 33472

American (AMR) AF: 0.291 AC: 13004 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 7898 AN: 26116

East Asian (EAS) AF: 0.368 AC: 14591 AN: 39676

South Asian (SAS) AF: 0.193 AC: 16618 AN: 86232

European-Finnish (FIN) AF: 0.449 AC: 23948 AN: 53374

Middle Eastern (MID) AF: 0.137 AC: 792 AN: 5764

European-Non Finnish (NFE) AF: 0.312 AC: 346299 AN: 1111482

Other (OTH) AF: 0.293 AC: 17663 AN: 60354

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

African (AFR) AF: 0.161 AC: 6686 AN: 41476

American (AMR) AF: 0.265 AC: 4059 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3464

East Asian (EAS) AF: 0.379 AC: 1945 AN: 5136

South Asian (SAS) AF: 0.196 AC: 942 AN: 4814

European-Finnish (FIN) AF: 0.464 AC: 4896 AN: 10560

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21035 AN: 67968

Other (OTH) AF: 0.241 AC: 510 AN: 2114

Alfa AF: 0.284 Hom.: 10003

Bravo AF: 0.253

Asia WGS AF: 0.314 AC: 1092 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.289

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

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