4-3160329-C-T

Position:

• chr4-3160329-C-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.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

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=-0.56).
• BP6: Variant 4-3160329-C-T is Benign according to our data. Variant chr4-3160329-C-T is described in ClinVar as [Benign]. Clinvar id is 1599466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3160329-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.3801C>T	p.Leu1267Leu	synonymous_variant	29/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.3801C>T	p.Leu1267Leu	synonymous_variant	29/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.3801C>T	p.Leu1267Leu	synonymous_variant	29/67	1	NM_001388492.1	ENSP00000347184.5

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

GnomAD3 exomes AF: 0.287 AC: 45697 AN: 159328 Hom.: 7211 AF XY: 0.281 AC XY: 23623 AN XY: 84152

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 SAS exome AF: 0.190

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

Gnomad4 AFR exome AF: 0.0468

Gnomad4 AMR exome AF: 0.277

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.373

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.428

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.282

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

Gnomad4 AFR AF: 0.0592

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.222

Alfa AF: 0.277 Hom.: 5297

Bravo AF: 0.220

Asia WGS AF: 0.304 AC: 1057 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 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.2
DANN	Benign	0.47

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: rs363099; hg19: chr4-3162056; COSMIC: COSV61870509; COSMIC: COSV61870509;