rs1065745

Positions:

• chr4-3121347-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001388492.1(HTT):​c.1188C>T​(p.Thr396=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,613,760 control chromosomes in the GnomAD database, including 2,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (478 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1728 hom.)
• Consequence: HTT NM_001388492.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.217

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 4-3121347-C-T is Benign according to our data. Variant chr4-3121347-C-T is described in ClinVar as [Benign]. Clinvar id is 1600856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.217 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.1188C>T	p.Thr396=	synonymous_variant	9/67	ENST00000355072.11
HTT	NM_002111.8	c.1194C>T	p.Thr398=	synonymous_variant	9/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.1188C>T	p.Thr396=	synonymous_variant	9/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10273 AN: 152090 Hom.: 473 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0753

Gnomad FIN AF: 0.0678

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0559

GnomAD3 exomes AF: 0.0469 AC: 11705 AN: 249534 Hom.: 383 AF XY: 0.0476 AC XY: 6442 AN XY: 135388

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0231

Gnomad ASJ exome AF: 0.0306

Gnomad EAS exome AF: 0.00534

Gnomad SAS exome AF: 0.0716

Gnomad FIN exome AF: 0.0654

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0433 AC: 63230 AN: 1461552 Hom.: 1728 Cov.: 31 AF XY: 0.0434 AC XY: 31573 AN XY: 727080

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0242

Gnomad4 ASJ exome AF: 0.0319

Gnomad4 EAS exome AF: 0.00426

Gnomad4 SAS exome AF: 0.0698

Gnomad4 FIN exome AF: 0.0619

Gnomad4 NFE exome AF: 0.0397

Gnomad4 OTH exome AF: 0.0478

GnomAD4 genome AF: 0.0676 AC: 10291 AN: 152208 Hom.: 478 Cov.: 32 AF XY: 0.0685 AC XY: 5098 AN XY: 74410

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0362

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.0752

Gnomad4 FIN AF: 0.0678

Gnomad4 NFE AF: 0.0414

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0522 Hom.: 150

Bravo AF: 0.0659

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.0334

EpiControl AF: 0.0379

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 24, 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	-0.39
CADD	Benign	9.3
DANN	Benign	0.39

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: rs1065745; hg19: chr4-3123074; COSMIC: COSV61868792; COSMIC: COSV61868792;