rs1065745

Variant names:

• chr4-3121347-C-T
• rs1065745
• NM_001388492.1:c.1188C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001388492.1(HTT):​c.1188C>T​(p.Thr396Thr) 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
• Publications: 8 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, ClinGen, Labcorp Genetics (formerly Invitae), 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 -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.1188C>T	p.Thr396Thr	synonymous	Exon 9 of 67	NP_001375421.1
	HTT	NM_002111.8		c.1188C>T	p.Thr396Thr	synonymous	Exon 9 of 67	NP_002102.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.1188C>T	p.Thr396Thr	synonymous	Exon 9 of 67	ENSP00000347184.5
	HTT	ENST00000681528.1		c.930C>T	p.Thr310Thr	synonymous	Exon 9 of 68	ENSP00000506116.1
	HTT	ENST00000680956.1		c.930C>T	p.Thr310Thr	synonymous	Exon 9 of 67	ENSP00000506029.1

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

GnomAD2 exomes AF: 0.0469 AC: 11705 AN: 249534 AF XY: 0.0476

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 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

African (AFR) AF: 0.132 AC: 4401 AN: 33464

American (AMR) AF: 0.0242 AC: 1083 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 834 AN: 26134

East Asian (EAS) AF: 0.00426 AC: 169 AN: 39700

South Asian (SAS) AF: 0.0698 AC: 6020 AN: 86252

European-Finnish (FIN) AF: 0.0619 AC: 3304 AN: 53418

Middle Eastern (MID) AF: 0.0643 AC: 371 AN: 5766

European-Non Finnish (NFE) AF: 0.0397 AC: 44162 AN: 1111714

Other (OTH) AF: 0.0478 AC: 2886 AN: 60380

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

African (AFR) AF: 0.133 AC: 5544 AN: 41534

American (AMR) AF: 0.0362 AC: 553 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3470

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5172

South Asian (SAS) AF: 0.0752 AC: 362 AN: 4816

European-Finnish (FIN) AF: 0.0678 AC: 718 AN: 10596

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0414 AC: 2816 AN: 68008

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0522 Hom.: 184

Bravo AF: 0.0659

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.0334

EpiControl AF: 0.0379

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	-0.39
CADD	Benign	9.3
DANN	Benign	0.39
PhyloP100		-0.22
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: rs1065745; hg19: chr4-3123074; COSMIC: COSV61868792; COSMIC: COSV61868792;