4-3160329-C-T

Variant names:

• chr4-3160329-C-T
• rs363099
• NM_001388492.1:c.3801C>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.3801C>T​(p.Leu1267Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,552,978 control chromosomes in the GnomAD database, including 71,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5646 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65628 hom.)
• Consequence: HTT NM_001388492.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.59
• Publications: 23 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.56).
• BP6: Variant 4-3160329-C-T is Benign according to our data. Variant chr4-3160329-C-T is described in ClinVar as Benign. ClinVar VariationId is 1599466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 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.3801C>T	p.Leu1267Leu	synonymous	Exon 29 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.3801C>T	p.Leu1267Leu	synonymous	Exon 29 of 67	NP_002102.4	P42858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.3801C>T	p.Leu1267Leu	synonymous	Exon 29 of 67	ENSP00000347184.5	P42858
	HTT	ENST00000510626.5	TSL:1	n.3900C>T		non_coding_transcript_exon	Exon 16 of 53
	HTT	ENST00000681528.1		c.3543C>T	p.Leu1181Leu	synonymous	Exon 29 of 68	ENSP00000506116.1	A0A7P0TAC5

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36523 AN: 152040 Hom.: 5641 Cov.: 32

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.215

GnomAD2 exomes AF: 0.287 AC: 45697 AN: 159328 AF XY: 0.281

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.300 AC: 420467 AN: 1400820 Hom.: 65628 Cov.: 32 AF XY: 0.297 AC XY: 205228 AN XY: 691090

African (AFR) AF: 0.0468 AC: 1498 AN: 31992

American (AMR) AF: 0.277 AC: 9939 AN: 35856

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7738 AN: 25164

East Asian (EAS) AF: 0.373 AC: 13598 AN: 36452

South Asian (SAS) AF: 0.187 AC: 14851 AN: 79384

European-Finnish (FIN) AF: 0.428 AC: 21194 AN: 49482

Middle Eastern (MID) AF: 0.124 AC: 708 AN: 5700

European-Non Finnish (NFE) AF: 0.310 AC: 334597 AN: 1078738

Other (OTH) AF: 0.282 AC: 16344 AN: 58052

GnomAD4 genome AF: 0.240 AC: 36530 AN: 152158 Hom.: 5646 Cov.: 32 AF XY: 0.243 AC XY: 18051 AN XY: 74374

African (AFR) AF: 0.0592 AC: 2460 AN: 41554

American (AMR) AF: 0.252 AC: 3846 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3470

East Asian (EAS) AF: 0.381 AC: 1965 AN: 5162

South Asian (SAS) AF: 0.190 AC: 917 AN: 4830

European-Finnish (FIN) AF: 0.441 AC: 4661 AN: 10574

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20861 AN: 67966

Other (OTH) AF: 0.222 AC: 467 AN: 2108

Alfa AF: 0.269 Hom.: 6815

Bravo AF: 0.220

Asia WGS AF: 0.304 AC: 1057 AN: 3478

ClinVar

ClinVar submissions

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	-0.56
CADD	Benign	5.2
DANN	Benign	0.47
PhyloP100		1.6
PromoterAI		0.014	Neutral
Mutation Taster		=100/0	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: rs363099; hg19: chr4-3162056; COSMIC: COSV61870509; COSMIC: COSV61870509;